Letter to the Editor

Oxidative Stress Might Reduce Essential Fatty Acids in Erythrocyte
Membranes of Chronic Fatigue Syndrome Patients

Nutritional Neuroscience, Volume 7 Number 4 (August 2004), pp.
251-253

JO NIJS [a,b,*] and KENNY DE MEIRLEIR [a]

Affiliations:
[a] Department of Human Physiology, Faculty of Physical Education and
Physical Therapy, Vrije Universiteit Brussel (VUB), Brussel, Belgium;
[b] Division of Musculoskeletal Physical Therapy, Department of Health
Sciences, Hogeschool Antwerpen (HA), Antwerpen, Belgium
[*] Corresponding author. Address: MFYS/SPORT KRO -I VUB, Laarbeeklaan 101,
B-1090, Brussel, Belgium. Tel.: +32-2-477-4604.
Fax: +32-2-477-4607. E-mail: <mailto:jo.nijs@vub.ac.be>jo.nijs@vub.ac.be

(Received 16 June 2004; Revised 19 July 2004; In final form 27 July 2004)


Conflicting results addressing reduced levels of two essential fatty acids
in the erythrocyte membrane of patients with chronic fatigue syndrome (CFS)
have been reported. The utilised diagnostic criteria for CFS may account
for the observed discrepancies among investiga­tors. Decreased levels of
essential fatty acids in the erythrocyte membrane of CFS patients fit our
current understanding of CFS pathophysiology. Activation of the protein
kinase R enzyme leads to nuclear factor-KB activation, which in turn
generates increased production of nitric oxide (NO). A wide variety of
infectious agents are typically seen in CFS patients, and are able to
increase NO production. It is hypothesized that oxidative stress accounts
for the observed reduction in the levels of essential fatty acids in the
erythrocyte membrane of CFS patients.

Keywords: Chronic fatigue syndrome; Oxidative stress; Nitric oxide;
Erythrocyte membrane; Pathophysiology


In last years' December issue of the Journal, Liu et al. (2003) showed that
the levels of two essential fatty acids in the erythrocyte membrane were
decreased in patients with chronic fatigue syndrome (CFS), compared to age-
and sex-matched healthy controls. They studied blood samples taken from 42
CFS patients and 37 controls; lipid analysis was performed in order to
examine the essential fatty acids levels in the erythrocyte membranes. It
was shown that the levels of arachidonic acid and docosahexanoic acid (both
essential fatty acids) were decreased in the CFS patients compared to the
control group. 

In the Discussion section, the authors speculate that either
oxidative stress or insufficient ingestion of fatty acids might account for 
these erythrocyte membrane alterations in CFS patients. We agree with the 
authors that evidence supporting a role for oxidative stress in CFS is 
accumulating. In this manuscript, it is outlined how oxidative stress fits 
our current understanding of CFS pathophysiology, and how it might explain 
the observations done by Liu et al. (2003).

Firstly, we would like to congratulate the authors for their work, they
have addressed an important issue and provided new compelling evidence
supportive of a biological nature for the dibilitating condition known as
CFS. As reviewed in the Introduction section, previous studies revealed
conflicting evidence addressing levels of essential fatty acids in
erythrocyte membranes of CFS patients. The authors correctly indicated that
the utilised diagnostic criteria might account for the observed
differences. Indeed, while Behan and Bakheit (1991) found decreased levels
of essential fatty acids in erythrocyte membranes of CFS patients, Warren
et al. (1999) were unable to confirm these results. The latter study used
the Oxford criteria to define the CFS patients, while Liu et al. (2003)
used the CDC (Centre for Disease Control and Prevention) case definition
for CFS (Fukuda et al., 1994), but failed to correctly refer to the
original publication of these diagnostic criteria (instead of referring to
the original report published in the Annals of Internal Medicine in 1994,
they referred Harrison's Principles of Internal Medicine (Strauss, 1998)).
Compared to the 1994 CDC criteria for CFS (Fukuda et al., 1994), Sharpe et
al. (1991) describe a much broader definition of CFS. British CFS
researchers have chosen not to include symptoms of depressive illness and
anxiety disorders as exclusion factors, for they consider these symptoms to
be central and debilitating aspects of the syndrome (Sharpe et al., 1991).
Additionally, they used fewer symptom criteria for it has been argued that
no symptoms have been shown to be specific for CFS (Hickie et al., 1995).
Consequently, extrapolation of research results addressing Sharpe et al.
(1991) defined CFS patients to Fukuda et al. (1994) defined subjects may be
inappropriate. This underscores the appropriateness and importance of the
study by Liu et al. (2003).

It was shown that the levels of arachidonic acid and docosahexanoic acid in
the erythrocyte membranes of CDC-defined CFS patients were decreased
compared to the healthy controls (Liu et al., 2003). As correctly explained
in the Discussion section, oxidative stress leads to excessive oxidation
and consequent reduced levels of fatty acids in cell membranes,
hypothetically explaining the observed depleted fatty acids levels in
erythrocyte membranes of CFS patients. Evidence supporting a role for
oxidative stress in CFS is accumulating. Elevated nitric oxide (NO) levels
have been documented in CFS patients by Kurup and Kurup (2003), and
oxidative stress has found to be associated with symptom expression in CFS
patients (Richards et al., 2000). Moreover, Fulle et al. (2000) provided
prelimi­nary evidence supporting the view that lipids are the cellular
targets of oxidative stress in muscle cells of CFS patients. Recent
research provided insight into the aetiology of oxidative stress in CFS
patients.

The deregulation of the 2',5'-oligoadenylate (2-5A) synthetase/RNase L
pathway in subsets of CFS patients has been reported at length in the
scientific literature (Suhadolnik et al., 1994; De Meirleir et al., 2000).
Elastases and calpain are capable of initiating high molecular weight RNase
L (83 kDa) proteolysis, generating two major fragments with molecular
masses of 37 (a truncated low molecular weight RNase L) and 30 kDa
respectively (Demettre et al., 2002) (Fig. 1). Besides triggering the 2-5A
synthetase/RNase L activation, type I interferons induce the expression of
the double-stranded RNA dependent protein kinase R (PKR). Activation of
this enzyme, as typically seen during viral infection or cellular stress,
results in a blockade of protein synthesis and consequent cell death
(apoptosis). Experimental data point to an activation of the PKR enzyme,
parallel to the 83 kDa RNase L proteolysis, in subsets of CFS (Englebienne
et al., 2001). PKR activation leads to phosphorylation of the inhibitor of
NF (nuclear factor)-KB (IKB) and consequent NF-KB activation, which in turn
causes inducible NO synthetase (iN OS) expression (Uetani et al., 2000).
iNOS generates increased production of NO by monocytes/macrophages, thus
explaining oxidative stress in CFS patients.

PKR-dependent elevated NO-levels might be caused by a wide variety of
infectious agents, as typically observed in CFS patients. An increased
prevalence of Mycoplasma infections in CFS patients compared to healthy
subjects has consistently been reported in the scientific literature
(Vojdani et al., 1998; Nasralla et al., 1999; Nijs et al., 2002). Among the
different Mycoplasma species studied, Mycoplasma fermentans is one of the
most prevalent in patients with CFS. M. fermentans produces a lipopeptide,
named 2-kDa macrophage-activating lipopeptide (MALP-2), which stimulates
macrophages (Pall and Satterle, 2001). Macrophages, activated by MALP-2,
release NO (Piec et aI., 1999; Rawadi, 2000; Takeuchi et aI., 2000).
Furthermore, NO is synthesized in response to, and has potent antiviral
activity against a number of viruses, for instance Epstein-Barr virus
(Mannick et aI., 1994) and Coxsackie B virus (Zaragoza et aI., 1997). Both
Epstein - Barr virus and Coxsackie B virus have been suggested as cofactors
in CFS pathophy­siology; an infection of the B lymphocytes by Epstein -
Barr virus has long been considered the cause of CFS (Levy, 1994), while
antibodies to Coxsackie B virus are commonly found in blood samples taken
from CFS patients (Bell et aI., 1988; Yousef et aI., 1988).

Taken together, evidence for elevated NO levels in CFS patients has been
provided, and this observation fits our current understanding of CFS
pathophysiology. Oxidative stress, through oxidation, might well account
for the decrease of essential fatty acids in the erythrocyte membranes as
observed by Liu et aI. (2003). Further studying of these hypothetical
interactions between depleted fatty acids in cell membranes and oxidative
stress in CDC-defined CFS patients is warranted.

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__________________________
FIGURE 1 Immunopathology of CFS. IFN, interferon; 2-5A, 2',
5'-oligoadenylate; PKR, protein kinase R; NF, nuclear factor; NO, nitric oxide.