Novel chronic fatigue syndrome (CFS) theory finally produces
detailed explanations for many CFS observations
novel theory of the cause of CFS has been published which is
supported by diverse biochemical and physiological observations
of CFS, while providing explanations for five of most difficult
puzzles about this medical condition. The theory has been
published by Dr. Martin L. Pall (Professor of Biochemistry and
Basic Medical Sciences, Washington State University) in several
publications (1-4,9). The theory starts with the observation
that infections that precede and may therefore induce CFS and
related conditions act to induce excessive production of
inflammatory cytokines that induce, in turn, the
inducible nitric oxide synthase (iNOS). This enzyme, in
turn, synthesizes excessive amounts of nitric oxide which
reacts with another compound (superoxide) to produce the
potent oxidant peroxynitrite (see Fig. 1).
Peroxynitrite acts via six known biochemical mechanisms to
increase the levels of both nitric oxide and superoxide which
react to produce more peroxynitrite (Fig. 1). In this way, once
peroxynitrite levels are elevated, they may act to continue the
elevation, thus producing a self-sustaining vicious cycle
(ref.1). It is this cycle, according to the theory, that
maintains the chronic symptoms of CFS and it is this cycle,
therefore, that must be interrupted to effectively treat this
Twelve different observations on chronic fatigue syndrome and
its symptoms provide support for this theory:
The levels of neopterin, a marker for the induction of the
inducible nitric oxide synthase are reported to be elevated in
Mitochondria are reported to be dysfunctional in CFS and
mitochondria are known to be attacked by peroxynitrite and also
by nitric oxide (1).
Both cis-aconitate and succinate levels are reported to be
elevated in CFS and the enzymes that metabolize these two
compounds are known to be inactivated by peroxynitrite (1).
The four inflammatory cytokines implicated have been reported to
been reported to be elevated in 10 different studies of CFS
These same inflammatory cytokines have been reported to induce
fatigue when injected into humans (1).
An animal (mouse) model of CFS has "fatigue" induced by a
bacterial extract that can induce both the inflammatory
cytokines and also the inducible nitric oxide synthase.
Polyunsaturated fatty acid pools are reported to be depleted in
CFS and such polyunsaturated fatty acids are known to be
oxidized by oxidants such as peroxynitrite.
Anecdotal evidence has suggested that antioxidants such as
coenzyme Q-10, flavonoids and glutathione precursors may be
useful in CFS treatment, consistent with a role for an oxidant
such as peroxynitrite.
Women are reported to produce more nitric oxide than men,
possibly explaining the gender bias seen in CFS. A similar
gender bias is seen in autoimmune diseases characterized by
excessive peroxynitrite (i.e. lupus, rheumatoid arthritis).
Cases of CFS are associated with high levels of deleted
mitochondria DNA, suggesting but not proving that mitochondrial
dysfunction can produce the symptoms of CFS (1).
Biochemical similarities – depletion of glutamine and cystine
pools – have been reported in CFS and several diseases
characterized by elevated peroxynitrite levels, suggesting a
similar biochemical basis for all of these conditions (1).
Because peroxynitrite is a potent oxidant, this theory predicts
that oxidative stress will be elevated in CFS. There was no
direct evidence for this when the theory was published but three
subsequent papers have reported substantial evidence for such
oxidative stress in CFS (5-7A). These results, may therefore, be
considered to confirm important predictions of the theory,
although the authors were unaware of this theory when they
initiated these studies.
CFS puzzles explained by the elevated nitric oxide/peroxynitrite
There are five different puzzles of CFS that are
explained by this theory. The first of these, the chronic
nature of CFS, is explained by the self-sustaining vicious cycle
that is central to this theory. The second is how
infection and other stress which often precede CFS may produce
CFS. This theory predicts that each of these can lead into this
mechanism by inducing excessive nitric oxide. Infection is not
the only stress that may be involved in this way – both
physical trauma and severe psychological trauma can produce
excessive nitric oxide synthesis (2). In addition, tissue
hypoxia may induce this cycle by increasing levels of superoxide
(the other precursor of peroxynitrite) (2).
A third puzzle about CFS is how it leads to the many
biochemical/physiological correlates reported to occur in CFS.
This is discussed with the list of 12 such correlates described
A fourth puzzle about CFS is how the diverse symptoms of
this condition may be generated. It turns out that a variety of
factors, including nitric oxide, superoxide, oxidative stress
and mitochondrial/energy metabolism dysfunction may have
important roles (2). For example, nitric oxide is known to
stimulate the nociceptors that initiate the perception of pain,
and therefore excessive nitric oxide may cause the multi-organ
pain associated with CFS (2). Nitric oxide has a central role in
learning and memory and so its elevation may also provide a
partial explanation for the cognitive dysfunction characteristic
of CFS (2). Other symptoms explained by this theory include
orthostatic intolerance, immune dysfunction, fatigue and
post-exertional malaise (2). The immune dysfunction reported in
CFS, may allow for opportunistic infections to develop, such as
mycoplasma or HHV6 infections, which may exacerbate the basic
CFS mechanism by increasing inflammatory cytokine synthesis.
What about multiple chemical sensitivity, posttraumatic stress
disorder and fibromylagia?
A fifth puzzle regarding CFS is its variable symptoms and,
most importantly, its association with three other
conditions of equally puzzling etiology, multiple chemical
sensitivity (MCS), posttraumatic stress disorder (PTSD) and
fibromylagia (FM). The theory explains the variable symptoms,
from one case to another, in part, by a somewhat variable tissue
distribution of the elevated nitric oxide/peroxynitrite.
A common etiology (cause) for CFS with MCS, PTSD and FM has been
suggested by others (discussed in refs 4,9). A common causal
mechanism for these four conditions is suggested not only by the
association among these different conditions (many people are
afflicted by more than one) but also by the overlapping symptoms
typically found in these four conditions (see refs. 4 and 9 for
discussion). These overlaps raise the question about whether
MCS, FM and PTSD may be caused by excessive nitric oxide and
peroxynitrite. Each of these four conditions is reported to
be often preceded by and possibly induced by exposure to a
relatively short-term stress that can induce excessive nitric
Pall and Satterlee (4) present a substantial case for an
excessive nitric oxide/peroxynitrite cause for multiple chemical
sensitivity (MCS), including the following:
Organic solvents and pesticides whose exposure is
reported to precede and presumably induce multiple
chemical sensitivity, are also reported to induce
excessive nitric oxide synthesis. Such chemicals are
also reported to induce increased synthesis of
inflammatory cytokines which induce, in turn, the
inducible nitric oxide synthase (leading to increased
synthesis of nitric oxide).
Neopterin, a marker of induction of the inducible nitric
oxide synthase, is reported to be elevated in MCS.
Markers of oxidative stress are reported to be elevated
in MCS, as predicted if excessive peroxynitrite is
In animal models of MCS, there is convincing evidence
for an essential role for both excessive NMDA
activity (where such activity is known to induce
excessive nitric oxide) and for excessive nitric oxide
synthesis itself. If one blocks the excessive nitric
oxide synthesis in these animal models, the
characteristic biological response is also blocked. This
and other evidence shows the nitric oxide has an
essential role (4).
Somewhat similar evidence is available suggesting an elevated
nitric oxide/peroxynitrite mechanism for both PTSD and FM (9).
PTSD is thought to be induced by excessive NMDA stimulation,
which, as discussed above, is known to produce excessive nitric
oxide and peroxynitrite (9). Two inflammatory cytokines known to
induce increased synthesis of nitric oxide have been reported to
be elevated in PTSD. PTSD animal model studies have reported an
essential role for both excessive NMDA stimulation and nitric
oxide synthesis in producing the characteristic biological
Interestingly, a recent study of FM implicates elevated nitric
oxide and also elevated NMDA stimulation (8), and such NMDA
stimulation is known to increase nitric oxide synthesis. As in
the other conditions discussed here, there is a pattern of
evidence from studies of FM patients, consistent with the
proposed nitric oxide/peroxynitrite mechanism (9). The theory
that elevated nitric oxide/peroxynitrite is responsible for the
etiology of CFS, MCS, PTSD and FM appears to be the only
mechanism to be proposed that explains the multiple overlaps
among these four conditions. While the pattern of evidence
supporting it cannot be considered definitive, the many types of
evidence providing support for this view must be considered
What does this proposed mechanism suggest about CFS treatment?
As discussed in ref 1, there are a number of agents that may be
useful in the treatment of CFS, based primarily on anecdotal
evidence, that are expected to lower the consequences of the
proposed nitric oxide/peroxynitrite mechanism. Possibly the most
intriguing such mechanism relates to the widespread use of
vitamin B12 injections in treatment of CFS (3). Two forms of
vitamin B12 are being used here, hydroxocobalamin, which is a
nitric oxide scavenger and cyanocobalamin, which is converted to
hydroxocobalamin by Pall human cells (3). These observations
suggest that the nitric oxide/peroxynitrite proposed mechanism
for CFS makes useful predictions for effective treatment. It is
hoped that this proposed mechanism may allow us to optimize the
use of these and other agents for treatment of CFS and related
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