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Novel Chronic Fatigue Syndrome (CFS) Theory Finally Produces Detailed Explanations for Many CFS Observations
(Reprinted with author's permission.)
By Martin L. Pall
( phone: 509-335-1246)
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:
CFS puzzles explained by the elevated nitric oxide/peroxynitrite theory:
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 the following:
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 as follows:
1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chrnnic fatigue syndrome. Medical Hypotheses 2000;54:115-125.