Long‐chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome)

Abstract

Evidence is put forward to suggest that myalgic encephalomyelitis, also known as chronic fatigue syndrome, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesise n‐3 and n‐6 long‐chain polyunsaturated fatty acids by inhibiting the δ‐6 desaturation of the precursor essential fatty acids—namely, α‐linolenic acid and linoleic acid. This would, in turn, impair the proper functioning of cell membranes, including cell signalling, and have an adverse effect on the biosynthesis of eicosanoids from the long‐chain polyunsaturated fatty acids dihomo‐γ‐linolenic acid, arachidonic acid and eicosapentaenoic acid. These actions might offer an explanation for some of the symptoms and signs of myalgic encephalomyelitis. A potential therapeutic avenue could be offered by bypassing the inhibition of the enzyme δ‐6‐desaturase by treatment with virgin cold‐pressed non‐raffinated evening primrose oil, which would supply γ‐linolenic acid and lipophilic pentacyclic triterpenes, and with eicosapentaenoic acid. The γ‐linolenic acid can readily be converted into dihomo‐γ‐linolenic acid and thence arachidonic acid, while triterpenes have important free radical scavenging, cyclo‐oxygenase and neutrophil elastase inhibitory activities. Furthermore, both arachidonic acid and eicosapentaenoic acid are, at relatively low concentrations, directly virucidal.

The aetiology of myalgic encephalomyelitis (chronic fatigue syndrome) is currently not known. In this paper, evidence is adduced to show the key role of certain long‐chain polyunsaturated fatty acids in the pathophysiology of this disease. Firstly, evidence suggesting a viral aetiology is provided. Secondly, the effects of such viral infections on the human biosynthetic pathways for long‐chain polyunsaturated fatty acids are considered. Thirdly, the subsequent effects on membrane phospholipids and the immune system are described. Finally, therapeutic implications are outlined.

Viral aetiology

Several converging lines of evidence point to a viral aetiology for myalgic encephalomyelitis.

Firstly, many clinical features of epidemics of myalgic encephalomyelitis‐like illnesses, such as the Los Angeles County Hospital epidemic of 1934 and the Royal Free Hospital epidemic of 1955, are consistent with viral infections.¹

Secondly, immune system changes in myalgic encephalomyelitis tend to point to reduced natural killer cell activity, reduced Th1 cell activity, increased Th2 cell activity and increased cytotoxic T cell activity.¹,²,³,⁴,⁵,⁶ These findings are consistent with those of a pre‐existing long‐term viral infection. Although these findings are also consistent with an autoimmune response, there is little consistent evidence to support this possibility in myalgic encephalomyelitis.

The third line of evidence relates to blood fatty acid levels. As described later, viral infections can impair the ability of the mammalian body to biosynthesise long‐chain polyunsaturated fatty acids from their short‐chain precursors. In the baseline comparison of erythrocyte membrane fatty acid levels among 63 patients (with what was then termed postviral fatigue syndrome) and 32 normal volunteers, Behan et al⁷ found considerably lower levels of arachidonic acid, adrenic acid and the total n‐6 polyunsaturated fatty acids. Warren et al⁸ used the Oxford Criteria for diagnosis and found a considerably lower level of eicosapentaenoic acid in patients with chronic fatigue syndrome.

The fourth line of evidence comes from proton neurospectroscopy studies. As described in the next section, viral infections can prevent the body from biosynthesising long‐chain polyunsaturated fatty acids. In turn, this impairs the biosynthesis of membrane phospholipid molecules in the brain, as long‐chain polyunsaturated fatty acids are key components at the Sn2 position of these molecules. This leads to a reduced incorporation of the polar head group choline in these molecules (at the Sn3 position). Hence, we should expect to see a raised level of free choline in the brain, which can be assessed using proton neurospectroscopy.⁹ This is indeed the finding from the first two systematic proton neurospectroscopy studies thus far published on myalgic encephalomyelitis or chronic fatigue syndrome—one by our group¹⁰ and the other by the Glasgow group then headed by Chaudhuri.¹¹ Furthermore, in their report of a Japanese case series of three children with juvenile myalgic encephalomyelitis, Tomoda et al¹² have also reported a raised level of the choline peak on proton neurospectroscopy.¹²

The most recent evidence comes from an elegant study by Kaushik et al.¹³ They studied gene expression in peripheral blood mononuclear cells in 25 patients with chronic fatigue syndrome compared with 25 normal blood donors matched for age, sex and geographical location. One of their findings was up regulation of the mitochondrial translation initiation factor EIF4G1 transcript variant 5: a result that is consistent with a persistent virus infection.

Effects on biosynthetic pathways for long‐chain polyunsaturated fatty acids

The first step in humans in the biosynthesis of n‐6 long‐chain polyunsaturated fatty acids from the 18‐carbon short‐chain essential fatty acid precursor linoleic acid is catalysed by the enzyme δ‐6‐desaturase.¹ Similarly, the biosynthesis of n‐3 long‐chain polyunsaturated fatty acids from the 18‐carbon short‐chain essential fatty acid precursor α‐linolenic acid is also catalysed by δ‐6‐desaturase.¹ Back in 1935, Stoesser¹⁴ reported that acute viral infections were associated with a reduction in the levels of long‐chain polyunsaturated fatty acids. That the cause of this reduction was the ability of many viral species to inhibit the δ‐6 desaturation of the precursor short‐chain essential fatty acids was discovered four decades later by Dunbar and Bayley.¹⁵,¹⁶

Effects on membrane phospholipids and the immune system

The phospholipid molecule is the fundamental building block of the lipid bilayers of outer cell membranes and of many intracellular organelles. Based on a 3‐carbon glycerol backbone, in normal membranes, the middle carbon (the Sn2 position) should have a long‐chain polyunsaturated fatty acid attached to it, which is usually either the n‐6 arachidonic acid or the n‐3 docosahexaenoic acid. Attached ultimately to the Sn3 position is a polar head group, such as choline, ethanolamine, serine or inositol. As a result of viral, or other, inhibition of δ‐6‐desaturase, an inadequate supply of the long‐chain polyunsaturated fatty acids is available for incorporation into the membrane phospholipid molecules. Thus the ratio of anabolism to catabolism of membrane phospholipids can be expected to change in an adverse direction. In turn, as far as the brain is concerned, this may be expected to have an unfavourable effect on neurotransmission—for example, it has been shown that minor changes in fatty acid structure in a small proportion of membrane phospholipids can lead to profound changes in the tertiary and quaternary structures of membrane proteins, and in the functioning of such proteins.¹⁷,¹⁸

As mentioned above, changes in free choline can be measured in vivo using proton neurospectroscopy. Changes in the membrane phospholipid metabolism may also be indexed using phosphorus‐31 neurospectroscopy.⁹

In addition to the adverse effects on membrane structure and functioning caused by inhibition of δ‐6‐desaturase, there are also negative consequences with respect to the biosynthesis of eicosanoids, such as prostaglandins, leucotrienes and thromboxanes, as these require long‐chain polyunsaturated fatty acids such as arachidonic acid and eicosapentaenoic acid as their precursors.¹ In turn, this can compromise the functioning of the immune system.

Therapeutic implications

Inhibition of δ‐6‐desaturase can be bypassed by treatment with a combination of evening primrose oil, which supplies the n‐6 long‐chain polyunsaturated fatty acid γ‐linolenic acid, from which dihomo‐γ‐linolenic acid and arachidonic acid can be biosynthesised, and the n‐3 long‐chain polyunsaturated fatty acid eicosapenteanoic acid.

Take‐home messages

• Myalgic encephalomyelitis (chronic fatigue syndrome) may result from a persistent viral infection.

• It is worthwhile trying a course of ultra‐pure EPA with virgin evening primrose oil in patients.

• A daily dose of between two and eight VegEPA capsules should be tried for at least 3 to 6 months.

• Vitamin cofactors which may be helpful when using fatty acid treatment include biotin, niacin, folic acid, vitamin B6, vitamin B12 and vitamin C.

• Mineral cofactors which may be helpful when using fatty acid treatment include selenium, zinc and magnesium.

A further advantage of treatment with this combination relates to the finding that arachidonic acid and eicosapentaenoic acid, in addition to being precursors of many eicosanoids, are also directly virucidal at relatively low levels—for example, by inactivating lipid‐enveloped viruses.¹⁹,²⁰ Furthermore, the antiviral actions of interferons may also require the activation of the conversion, catalysed by cyclo‐oxygenase, of dihomo‐γ‐linolenic acid and arachidonic acid into eicosanoids.²¹

In administering this regimen, it is more advantageous to use virgin, cold‐pressed non‐raffinated evening primrose oil rather than the more commonly available refined preparation, as the virgin evening primrose oil is rich in lipophilic pentacyclic triterpenes, which have free radical scavenging, cyclo‐oxygenase and neutrophil elastase inhibitory properties.²²

Conclusion

Evidence suggests that myalgic encephalomyelitis or chronic fatigue syndrome may be associated with a persistent viral infection. Such an infection could adversely affect the biosynthesis of long‐chain polyunsaturated fatty acids and therefore the membrane structure, functioning and production of eicosanoids. Treatment with long‐chain polyunsaturated fatty acids may offer a potential therapeutic route.