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Novel Chronic Fatigue Syndrome (CFS) Theory Finally
Produces Detailed Explanations for Many CFS Observations
By Dr. Martin L. Pall
Professor of Biochemistry and Basic Medical Sciences
Washington State University
A novel theory of the cause of Chronic Fatigue Syndrome (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.
Peroxynitrite acts via six known biochemical mechanisms to increase the
levels of both nitric oxide and superoxide which react to produce more
peroxynitrite. 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 condition.
Twelve different observations on chronic fatigue syndrome and its
symptoms provide support for this theory:
1. The levels of neopterin, a marker for the induction of the inducible
nitric oxide synthase are reported to be elevated in CFS (1).
2. Mitochondria are reported to be dysfunctional in CFS and mitochondria are
known to be attacked by peroxynitrite and also by nitric oxide (1).
3. 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).
4. The four inflammatory cytokines implicated have been reported to be
elevated in 10 different studies of CFS (1,2).
5. These same inflammatory cytokines have been reported to induce fatigue
when injected into humans (1).
6. 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.
7. Polyunsaturated fatty acid pools are reported to be depleted in CFS and
such polyunsaturated fatty acids are known to be oxidized by oxidants such
8. Anecdotal evidence has suggested that antioxidants such as coenzyme Q10,
flavonoids and glutathione precursors may be useful in CFS treatment,
consistent with a role for an oxidant such as peroxynitrite.
9. 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 (e.g., lupus,
10. 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).
11. 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).
12. 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 above.
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 fibromyalgia?
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 oxide synthesis.
Pall and Satterlee (4) present a substantial case for an excessive nitric
oxide/peroxynitrite cause for multiple chemical sensitivity (MCS), including
• 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
• 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 involved.
• 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 that 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 response.
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 to be highly suggestive.
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 conditions.
Other sites with thoughtful presentations that you may wish to access are
1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic
fatigue syndrome. Medical Hypotheses 2000;54:115-125.
2. Pall ML. Elevated peroxynitrite as the cause of chronic fatigue syndrome:
Other inducers and mechanisms of symptom generation. Journal of Chronic
Fatigue Syndrome, 2000;7:45-58.
3. Pall ML. Cobalamin used in chronic fatigue syndrome therapy is a nitric
oxide scavenger. Journal of Chronic Fatigue Syndrome, 2001;8:39-44.
4. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for
the common etiology of multiple chemical sensitivity, chronic fatigue
syndrome and posttraumatic stress disorder. Annals of the New York Academy
of Science, 2001;933:323-329.
5. Richards RS, Roberts TK, Mathers MB, Dunstan RH, McGregor NR, Butt HL.
Investigation of erythrocyte oxidative damage in rheumatoid arthritis and
chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 2000;6:37-46.
6. Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. Blood
parameters indicative of oxidative stress are associated with symptom
expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.
7. Fulle S, Mecocci P, Fano G, Vecchiet I, Vecchini A, Racciotti D,
Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. Specific oxidative
alterations in vastus lateralis muscle of patients with the diagnosis of
chronic fatigue syndrome. Free Radicals in Biology and Medicine
7A. Keenoy BM, Moorkens G, Vertommen J, DeLeeuw I. Antioxidant strotus and
lipoprotein oxidation in chronic fatigue syndrome. Life Sciences
8. Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the
concentrations of amino acids in the cerebrospinal fluid that correlate with
pain in patients with fibromyalgia: implications for nitric oxide pathways.
9. Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia,
chronic fatigue syndrome and multiple chemical sensitivity via elevated
nitric oxide/peroxynitrite. Medical Hypotheses, 2001;57:139-145.
(c) Dr. Martin L. Pall. This article is reprinted with the author's
permission. For more information, please visit http://molecular.biosciences.wsu.edu/Faculty/pall.html.
This comes from ImmuneSupport.com, which is a privately owned American firm
that sells orthomolecular medicine. It caters especially to people with ME/CFS
and has useful regular information for patients with ME/CFS.
I do not know whether the theory is true and since it is very new it will
need testing, discussion and experimenting, but it is good sensible science of
the type I like, since I have been convinced for 20 years that the best hope
for patients with ME is a good biochemical theory that accounts for the