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| Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses
A Common Causal (Etiologic) Mechanism for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, Multiple Chemical Sensitivity, Fibromyalgia and Post-Traumatic Stress Disorder
Martin L. Pall, Professor Emeritus of Biochemistry and Basic Medical Sciences,
Washington State University and Research Director, The Tenth Paradigm Research Group.
Specific web pages:
Multiple Chemical Sensitivity
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Other Proposed NO/ONOO- Cycle Diseases
Approaches to Therapy
These four illnesses, chronic fatigue syndrome (CFS/ME), multiple chemical sensitivity (MCS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD) often occur together in the same individuals (they are comorbid) and share many symptoms in common (1,2). They also share a common pattern of case initiation: Each is often initiated (that is started) by a short-term stressor only to be followed by chronic illness that typically lasts for years and most often for life. These various similarities and overlaps among these four have led many scientists to suggest that they may share a common etiology (cause), however they have been uncertain what the cause may be. I will call these four illnesses multisystem illnesses, following the lead of some others, and will challenge here the claims they are unexplained and that even their symptoms are unexplained. What many have called the Gulf War Syndrome is a combination of all four (3; Chapter 10, ref.1).
It is my goal for this web page, to provide a detailed explanation for their overall mechanism and provide a proposed mechanism for the many symptoms and signs that they share. In web pages linked to this one, I will discuss some specific features of these illnesses and how each of these specific features may be generated by this same basic mechanism. I also provide more detailed support for the NO/ONOO- cycle mechanism outlined on this main web page, in these other web pages. My overall goal, here, is to outline the understanding of these illnesses that is documented in much greater detail in my book, ¡°Explaining ¡®Unexplained Illnesses¡¯¡± (1), as well as in many other publications (2-12).
The stressors implicated in the initiation of these illnesses are summarized in Table 1.
Table 1. Illness: Stressors Implicated in Initiation of Illness
The stressors indicated in bold are the ones most commonly implicated for that specific illness. It should be noted that the majority of such stressors are implicated in the initiation of more than one illness.
We have, here, 17 diverse stressors implicated in initiating these illnesses, leading one to ask, how they may do so? What I have argued, in my book (1) and elsewhere (2-10), is that each of these can act to increase nitric oxide levels. Each is reported to increase the levels of nitric oxide, or in three cases where that has not been studied, to stimulate a process which is itself known to increase nitric oxide. This is a striking common response and leads to the question about how nitric oxide increases might lead to chronic illness? My answer to that question is that nitric oxide, acting primarily through its oxidant product peroxynitrite, initiates a biochemical vicious cycle that is responsible, in turn, for the chronic illness. We have, then, an initial cause of illness (short-term stressor or stressors) acting to start this vicious cycle, with the cycle responsible for causing the chronic phase of illness. We are now calling the cycle the NO/ONOO- cycle after the structures of nitric oxide (NO) and peroxynitrite (ONOO-) but pronounced no, oh no! The cycle mechanism is outlined in Figure 1:
Fig. 1 legend. Vicious (NO/ONOO-) cycle diagram. Each arrow represents one or more mechanisms by which the variable at the foot of the arrow can stimulate the level of the variable at the head of the arrow. It can be seen that these arrows form a series of loops that can potentially continue to stimulate each other. An example of this would be that nitric oxide can increase peroxynitrite which can stimulate oxidative stress which can stimulate NF-kappaB which can increase the production of iNOS which can, in turn increase nitric oxide. This loop alone constitutes a potential vicious cycle and there are a number of other loops, diagrammed in the figure that can collectively make up a much larger vicious cycle. The challenge, according to this view, in these illnesses is to lower this whole pattern of elevations to get back into a normal range. You will note that the cycle not only includes the compounds nitric oxide, superoxide and peroxynitrite but a series of other elements, including the transcription factor NF-kappaB, oxidative stress, inflammatory cytokines (in box, upper right), the three different forms of the enzymes that make nitric oxide (the nitric oxide synthases iNOS, nNOS and eNOS), and two neurological receptors the vanilloid (TRPV1) receptor and the NMDA receptor.
The arrows in Fig. 1 represent 22 different mechanisms by which one element of the cycle can increase the levels of another element of the cycle. In my book (1) and elsewhere (2-4, 7-10), I discuss each of these 22. Of these 19 are well-documented and well-accepted biochemistry with three others less well documented. I recently reviewed the evidence for these last three and each of the three are now substantially better documented than when my book was written (10). Overall, there is massive evidence for the mechanisms proposed for the cycle, but what must be questioned is the physiological relevance of the cycle to these multisystem illnesses. Does the NO/ONOO- cycle really explain much of the etiologic (causal) mechanism of these illnesses?
There are five principles underlying the NO/ONOO- cycle as an explanatory model:
Of these principles, we have discussed 1 and 2 above. Principle 3 predicts that the symptoms and signs of illness can be generated by elevation of one or more elements of the cycle. Some examples of how symptoms and signs of illness may be explained by the cycle are discussed below.
Principle 4 is so important that it takes up an entire chapter in my book (1). Because nitric oxide, superoxide and peroxynitrite, the three chemical compounds most central to the NO/ONOO- cycle have relatively short half lives in biological tissues, they don¡¯t diffuse very far from their site of origin in the body. Nitric oxide has the longest such half-life and it only diffuses about one millimeter from its origin or less. Furthermore, most of the mechanisms implicated by the arrows act at the cellular levels. The consequence of all of this is that the NO/ONOO- cycle may be elevated in one tissue of the body but an adjacent tissue may show little elevation and therefore have little impact by the cycle. This local nature of the cycle biochemistry means that we can have all kinds of variations in tissue impact from one patient to another, leading in turn to all kinds of variation in symptoms and signs from one individual to another. This striking variation in symptoms from one individual to another has been repeatedly been noted in these illnesses and has been one of the great puzzles about this group of illnesses. The variation can be easily explained by the local nature of the NO/ONOO- cycle mechanism.
The primarily local nature, outlined in Principle 4 does not imply that there are no systemic effects. The antioxidant depletion produced by local oxidative stress will be, to a substantial extent, systemic and some of the effects of the inflammatory cytokines are also systemic. These may, in turn, produce changes in neuroendocrine function and immune function that are also systemic. However the primary local nature helps us to understand the profound variations in symptoms and signs seen from one patient to another, how these different diseases may differ from one another and also differ from possible additional diseases that may share this NO/ONOO- cycle etiology, such as tinnitus (12).
Principle 5 states that the focus of therapy should be to down-regulate NO/ONOO- cycle biochemistry. In other words, therapy should focus on lowering the cause of illness, not just on treating symptoms. This is obviously an important principle for both patients suffering from these illnesses and for conscientious physicians or other medical care providers trying to treat them.
Two Additional NO/ONOO- Cycle Classes of Mechanisms
There are two important types of mechanisms that are important parts of the cycle but are NOT obvious from Fig. 1.
Firstly, there are several known mechanisms by which peroxynitrite, superoxide and nitric oxide can lower energy metabolism in mitochondria (the parts of the cells that generate energy in the form of ATP) (1,10). This lowering of energy metabolism is important both because it has a role in generating the symptoms of these diseases but also be because it is part of the cycle itself. Specifically, it has important roles in producing the increased NMDA activity and it probably also has an important role in producing elevated levels of intracellular calcium, a part of the cycle. There is substantial evidence for mitochondrial dysfunction in CFS/ME and fibromyalgia. And there is additional evidence from clinical trial studies that agents that improve mitochondrial function are helpful in the treatment of this group of illnesses.
A second important part of the cycle involves the depletion of a compound called tetrahydrobiopterin (often abbreviated BH4), a compound that it oxidized by peroxynitrite (1,11). BH4 is what is known as a cofactor in the nitric oxide synthases (NOSs), and tetrahydrobiopterin depletion produces what has been called partial uncoupling of the NOSs. When a NOS enzyme is missing BH4, it produces superoxide in place of nitric oxide. The consequence of this is that in cells and tissues that have high NOS activity and partial uncoupling, one has many adjacent enzyme molecules, some producing nitric oxide and others producing superoxide and these will react rapidly with each other to form more peroxynitrite. This will, in turn oxidize more BH4, producing more partial uncoupling. This reciprocal relationship between peroxynitrite and BH4 depletion is, then a potential vicious cycle within the larger NO/ONOO- cycle and may constitute the essential core of the cycle. Lowering of this central couplet will be expected to produce a clinical improvement in these diseases, but will produce an increase in nitric oxide. So while I think that the net effect of nitric oxide in these diseases is negative one, agents that increase nitric oxide by lowering this central couplet should be helpful.
A revised figure of the NO/ONOO- cycle is Diagrammed in Fig. 2 below, includes both of these additional types of mechanisms. In it peroxynitrite is abbreviated PRN and both BH4 depletion and ATP depletion are shown. Another thing is that in the upper left hand corner, the TRP receptors are shown. This is because it appears that two other members of the TRP family of receptors may have roles here, not just the vanilloid (TRPV1) receptor is shown in Fig. 1.
NO/ONOO- Cycle Mechanisms for the Generation of Shared Symptoms and Signs of Illness
It has been repeatedly claimed by many that these multisystem illnesses are unexplained and that even their symptoms and unexplained. Clearly for the NO/ONOO- cycle mechanism to be a plausible mechanism for these multisystem illnesses, it must be possible to explain the symptoms and signs of illness as being generated by one or more elements of the cycle. Such explanations are needed for both the specific symptoms and signs (discussed on the specific web pages) and the shared ones, discussed here. In Chapter 3 of my book, I discuss both the evidence for these shared symptoms and signs and how they may be generated by the NO/ONOO- cycle etiology. The mechanisms listed below are not presented as established mechanisms in these illnesses, but they are plausible mechanisms based on substantial scientific information. Each of these only occur in some multisystem illness sufferers, consistent with the striking variation of symptoms and signs that are a characteristic feature of these illnesses. Indeed it may be argued that the defining symptoms and signs of CFS/ME, MCS, FM and PTSD are found in all sufferers of each of these illnesses because we required them for the diagnosis.
Table 1-1 Explanations for Symptoms and Signs
Major Disease Paradigms
1. Infectious diseases.
2. Genetic diseases.
3. Nutritional deficiency diseases.
4. Hormone dysfunction diseases.
6. Autoimmune diseases.
7. Somatic mutation/selection (cancer).
8. Ischemic cardiovascular diseases.
9. Amyloid (including prion) diseases.
10. NO/ONOO- cycle diseases
1. Pall M.L. (2007) Explaining ¡°Unexplained Illnesses¡±: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromylagia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others. Harrington Park (Haworth) Press, New York.
2. Pall M.L. (2000) Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses 54,115-125.
3. Pall M.L. (2001) Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypotheses 57,139-145.
4. Pall M.L. (2002) NMDA sensitization and stimulation by peroxynitrite, nitric oxide and organic solvents at the mechanism of chemical sensitivity in multiple chemical sensitivity. FASEB J 16,1407-1417.
5. Pall M.L. (2008) Post-radiation syndrome as a NO/ONOO(-) cycle, chronic fatigue syndrome-like disease. Med Hypotheses 71: 537-541.
6. Pall M.L. (2006) The NO/ONOO- cycle as the cause of fibromyalgia and related illnesses: Etiology, explanation and effective therapy. In: New Research in Fibromyalgia, John A. Pederson, Ed., pp 39-59, Nova Science Publishers, Inc., Hauppauge, NY.
7. Pall M.L., Anderson J.H. (2004) The vanilloid receptor as a putative target of diverse chemicals in multiple chemical sensitivity. Arch Environ Health 59,363-372.
8. Pall M.L., Satterlee J.D. (2001) Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder. Ann N Y Acad Sci 933,323-329.
9. Pall M.L. (2009) The NO/ONOO- cycle mechanism as the cause chronic fatigue syndrome/myalgic encephalomyelitis. In: New Research in Chronic Fatigue Syndrome, John A. Pederson, Ed., Nova Science Publishers, Inc., Hauppauge, NY, in Press.
10. Pall M.L. (2009) Multiple chemical sensitivity: toxicological questions and mechanisms. Wiley & Sons, New York, in press.
11. Pall M.L. (2007) Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle. Med Hypotheses 69,821-825.
12. Pall M.L., Bedient S.A. (2007) The NO/ONOO- cycle as the etiological mechanism of tinnitus. Int Tinnitus J 13,99-104.
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