Omega 3 fatty acid hypothesis

Professor Basant Puri of Imperial College London has theorized that some of the symptoms of ME/CFS are caused by abnormal fatty acid metabolism and can be ameliorated by supplementation with high dose eicosapentaenoic acid (EPA) and evening primrose oil, a source of gamma-Linolenic acid (GLA).

Gray, et al posit a similar hypothesis whereby the core features of ME/CFS – including reduced natural killer cell function and exercise intolerance – may be due to abnormal production of eicosanoids, signaling molecules involved in inflammation that are produced from fatty acids found in cell membranes.

Mechanism
Puri theorizes that a persistent, low grade viral infection blocks the delta-6-desaturase enzyme, which is required for generating the long chain Omega-3 and Omega-6 polyunsaturated fatty acids such as DGLA, arachidonic acid and EPA. This in itself will cause a variety of symptoms including sleep disturbances and improper immune responses.

Moreover, EPA, a long chain Omega 3 acid, is both a precursor to interferons and is directly antiviral.

These fatty acids are also precursors to eicosanoids, signaling molecules that regulate growth during and after physical activity, inflammation or immunity after the intake of toxic compounds and pathogens, and act as messengers in the central nervous system.

Finally, deficiencies in arachidonic acid and docosahexaeonic acid (DHA) have deleterious effects on cell membranes. They lose their normal flexibility and become more rigid, affecting the protein receptor molecules and disrupting cell signaling. This causes cognitive impairment.

Puri points to several very small studies that found increased choline in specific areas of the brains of CFS patients, including the occipital cortex and basal ganglia as evidence of unspecified alterations in fatty acid metabolism.

Grey, et al have a similar theory. However, they think the impairment is not in the production of long chain fatty acids but rather the cleaving of long chain fatty acids from cell membrane to produce eicosanoids. They think that the immunological dysfunction and exercise intolerance seen in ME/CFS can be explained by an increased ratio of two eicosanoids, namely Leukotriene B4/Prostaglandin E2.

Moreover, the increased choline observed in studies of ME patients could be due to increased Phospholipase A2 activity and the breakdown of cell membranes.

Treatment
Puri recommends treatment with evening primrose oil, a source of GLA, and high dose EPA without DHA, such as VegEPA. Both EPA and GLA block the conversion of AA to inflammatory leukotrienes through various mechanisms.

Similarly, Grey, et al, citing studies in rheumatoid arthritis point out increasing dietary Omega 3's decreases the amount of AA and linoleic acid (LA) (Omega 6's that are substrates for LTB4) in the cell membrane, thus reducing LTB4 production. They note that dietary changes can take 12-18 weeks to manifest in clinical improvement. They do not distinguish between EPA and DHA supplementation.

Evidence
There is little direct evidence to support Puri's hypothesis and no large scale clinical trials evaluating his proposed treatment have been conducted. Further research is warranted.

EPA/AA ratios in CFS patients
A study of twenty-two patients (defined using the CDC criteria) and twelve controls found that CFS patients have significantly lower EPA/AA and Omega3/Omega 6 (ω3/ω6) ratios owing to substantially increased levels of Omega 6 fatty acids (but not lower Omega 3s). These ratios correlated with some of the items on the FibroFatigue scale such as pain, fatigue, and memory deficits. The study also found significant correlations between the ω3/ω6 ratio and lowered serum zinc levels and lowered mitogen-stimulated CD69 expression on CD3+, CD3+CD4+, and CD3+CD8+ T cells.

However, since patients have normal levels of EPA, it may not be that delta-6-desaturase is being blocked by viral activity as Puri hypothesizes but rather that AA is increased because it is being hydrolyzed by Phospholipase A2 (PLA2) to produce eicosanoids. Increased PLA2 activity is observed in many neurological conditions and in inflammatory disorders such as fibromyalgia.

EPA competes directly with AA for the phospholipase A2 enzyme (PLA2) and thus inhibits the production of inflammatory eicosanoids. Over time, it reduces the amount of AA available in cell membranes. This suggests a possible role for EPA in the treatment of diseases where increased PLA2 activity is observed.

Effects of fatty acid treatment
The evidence for fatty acid treatment is mixed, owing in part to varying research criteria and incomparable treatments.

A double-blind, placebo-controlled study of 63 patients with postviral fatigue syndrome found the 85% of patients found improvement at three months on Efamol Marine, a high Omega-6 formulation of evening primrose oil and fish oil (linoleic acid: 58%, GLA: 7.2%, EPA: 3.6%, and DHA: 2.4%). An attempt to replicate the study using Efamol Marine and the Oxford Criteria found no effect.

In a small case study of four patients diagnosed by the Fukuda criteria, Puri found that high dose EPA was associated with significant improvement after 12 weeks of treatment.

Fatty acids and viruses
In vitro studies have found polyunsaturated fatty acids kill Epstein-Barr virus. and herpes simplex virus. Long chain polyunsaturated fatty acids inactivate lipid-enveloped viruses

Alternative hypotheses
Patricia Kane thinks that diseases she classes as those of neurotoxicity (e.g., multiple sclerosis, Parkinson's, Chronic Fatigue Syndrome) often involve deficiencies of Omega 6 and arachidonic acid in cell membranes due in part to the over-expression of very long chain fatty acids. She believes that adding Omega 3's before Omega 6's are properly supplemented can be deleterious to health.