Source: Journal of Clinical Pathology
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Date:   August 29, 2006
URL:    http://jcp.bmjjournals.com/cgi/content/abstract/jcp.2006.042424v1
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Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic 
encephalomyelitis (chronic fatigue syndrome) 

BK Puri(*)
MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, 
London UK 
* Correspondence to: Professor BK Puri, MRI Unit, Hammersmith Hospital, Du 
  Cane Road, London W12 0HS, England, UK, basant.puri@csc.mrc.ac.uk 


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 biosynthesize n-3 and n-6 long-chain polyunsaturated fatty acids by
inhibiting the delta-6 desaturation of the precursor essential fatty acids
alpha-linolenic acid and linoleic acid. In turn, this would impair the
proper functioning of cell membranes, including cell signalling, and have an
adverse effect of the biosynthesis of eicosanoids from the long-chain
polyunsaturated fatty acids dihomo-gamma-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 may be offered by bypassing the inhibition of the enzyme
delta-6-desaturase by administering both virgin cold-pressed non-raffinated
evening primrose oil and eicosapentaenoic acid. The former would supply
gamma-linolenic acid and lipophilic pentacyclic triterpenes. The gamma-
linolenic acid can readily be converted into dihomo-gamma-linolenic acid and
thence arachidonic acid, while triterpenes have important free radical
scavenging, cyclooxygenase 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 illness. First, evidence is provided which suggests a viral aetiology.
Second, the effects of such viral infections on the human biosynthetic
pathways for long-chain polyunsaturated fatty acids is considered. Third,
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.

First, 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]

Second, immune system changes in myalgic encephalomyelitis tend to point to
reduced NK cell activity, reduced Th1 cell activity, increased Th2 cell
activity and increased Tc cell activity.[1-6] These findings are consistent
with 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 we shall
see in the next two sections, viral infections can impair the ability of the
mammalian body to biosynthesize long-chain polyunsaturated fatty acids from
their short-chain precursors. In their baseline comparison of erythrocyte
membrane fatty acid levels between 63 patients (with what was then termed
postviral fatigue syndrome) and 32 normal volunteers, Behan et al. found
significantly lower levels of arachidonic acid and adrenic acid and of the
total n-6 polyunsaturated fatty acids.[7] A more recent study using the
Oxford Criteria for diagnosis found a significantly lower level of
eicosapentaenoic acid in patients with chronic fatigue syndrome.[8]

The fourth line of evidence comes from proton neurospectroscopy studies. As
we shall see in the next section, viral infections can prevent the body from
biosynthesizing long-chain polyunsaturated fatty acids. In turn, this
impairs the biosynthesis of membrane phospholipid molecules in the brain,
since 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 evidence of 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 in myalgic encephalomyelitis or chronic fatigue
syndrome, namely the one by our group and that by the Glasgow group then
headed by Chaudhuri.[10,11] Furthermore, a Japanese case series of three
children with juvenile myalgic encephalomyelitis has also reported a raised
level of the choline peak on proton neurospectroscopy.[12]

The most recent evidence comes from an elegant study by Jonathan Kerr's
group.[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, gender and geographical location. One of their
findings was upregulation of the mitochondrial translation initiation factor
EIF4G1 transcript variant 5, a result which 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 catalyzed by the enzyme
delta-6-desaturase.[1] Similarly, the biosynthesis of n-3 long- chain
polyunsaturated fatty acids from the 18-carbon short-chain essential fatty
acid precursor alpha-linolenic acid is also catalyzed by
delta-6-desaturase.[1] Back in 1935, Stoesser reported that acute viral
infections were associated with a reduction in the levels of long-chain
polyunsaturated fatty acids.[14] That the cause of this was the ability of
many viral species to inhibit the delta-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 fundamental building block of the lipid bilayers of outer cell membranes
and of many intracellular organelles is the phospholipid molecule. Based on
a three-carbon glycerol backbone, in normal membranes the middle carbon (the
Sn2 position) should have a long-chain polyunsaturated fatty acid attached
to it. This is usually either the n-6 long-chain polyunsaturated fatty acid
arachidonic acid or the n-3 long-chain polyunsaturated fatty acid
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 delta-6-desaturase, an inadequate supply
of the long-chain polyunsaturated fatty acids is available for incorporation
into membrane phospholipid molecules. Thus the ratio of anabolism to
catabolism of membrane phospholipids can be expected to alter in an adverse
direction. In turn, so far as the brain is concerned, this may be expected
to have an unfavourable effect on neurotransmission; for example it has been
demonstrated that minor changes in fatty acid structure in a very 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 membrane phospholipid metabolism may
also be indexed using 31-phosphorus neurospectroscopy.[9]

In addition to the adverse effects on membrane structure and functioning
caused by delta-6-desaturase inhibition, there are also negative
consequences with respect to the biosynthesis of eicosanoids, such as
prostaglandins, leukotrienes and thromboxanes, since 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 delta-6-desaturase can be bypassed by administering a
combination of evening primrose oil, which supplies the n-6 long-chain
polyunsaturated fatty acid gamma-linolenic acid, from which
dihomo-gamma-linolenic acid and arachidonic acid can be biosynthesized, and
the n-3 long-chain polyunsaturated fatty acid eicosapentaenoic acid.

A further advantage of giving 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 inactivating lipid-enveloped viruses.[19,20] Furthermore, the
antiviral actions of interferon may also require its activation of the
conversion, catalyzed by cyclooxygenase, of dihomo-gamma-linolenic acid and
arachidonic acid into eicosanoids.[21]

If administering this regime, there are advantages in using virgin,
cold-pressed non-raffinated evening primrose oil rather than the more
commonly available refined preparation, as the former is rich in lipophilic
pentacyclic triterpenes, which have free radical scavenging, cyclooxygenase
and neutrophil elastase inhibitory properties.[22]
 

CONCLUSION 

There is evidence that myalgic encephalomyelitis or chronic fatigue syndrome
may be associated with a persistent viral infection. Such an infection could
adversely impact on the biosynthesis of long-chain polyunsaturated fatty
acids and therefore on membrane structure and functioning and the production
of eicosanoids. Administration of long- chain polyunsaturated fatty acids
may offer a potential therapeutic route.
 

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