Reprinted form the Journal of Advancement in Medicine, Volume 6, Number 2, Summer 1993
ABSTRACT: A hypothesis is proposed that chronic fatigue is a state of accelerated oxidative molecular injury. Evidence supporting the hypothesis includes the following: 1. Spontaneity of oxidation in nature is the basic cause of the aging process for organisms capable of aerobic respiration. Redox dysregulations represent the initial events that lead to clinical disease processes. 2. Incidence of chronic fatigue is increasing, as is the oxidant stress in the Earth's atmosphere. 3. Evidence for oxidative cell membrane injury in chronic fatigue is furnished by changes in intracellular and extracellular ions. 4. Immunologic abnormalities that occur in chronic fatigue are consistent with initial oxidative injury. 5. Commonality of association of antigens of HLA-DR3 region with chronic fatigue syndrome and with other immune disorders such as rheumatoid arthritis, pemphigus vulgaris, systemic lupus erythematosus, and IgA and gold nephropathies. 6. Direct morphologic evidence of increased oxidative stress on the cell membrane is shown by the fact that we have found membrane deformities in up to 80% of erythrocytes in blood from chronic fatigue syndrome patients. These deformities are quickly reversed by administering ascorbic acid intravenously. 7. Changes in electromyopotentials observed in chronic fatigue patients are consistent with intracellular ionic and membrane changes. 8. Clinical entities commonly associated with chronic fatigue are known to increase oxidative molecular stress. 9. Clinical evidence obtained with relief of fatigue and related muscle symptoms with the use of oral and intravenous antioxidant nutrient therapy. From a clinical standpoint, this model for the molecular basis of chronic fatigue is useful for making therapeutic decisions for successful management of chronic fatigue without drug regimens.
Undue fatigue is a well known phenomenon as a problem for the physician. It is often traced to George Beard's 1869 description of undue fatigue which he termed neurasthenia (1). Since then, undue fatigue has often been viewed as nervous weakness. The terms "Shirker's syndrome" and "Yuppie plague" represent attempts to cloak this bias in contemporary vernacular. Since Beard's description, the search for the cause of chronic fatigue has often focused on infection with a host of organisms, including Brucella, Epstein-Barr virus and, more recently, retroviruses.
In 1985, a group of investigators at the Centers for Disease Control (CDC) formulated a set of criteria for the diagnosis of what they called chronic fatigue syndrome (CFS)!2). These criteria have done little to elucidate the true cause of the syndrome, but have served as a diagnostic label to test the efficacy of therapeutic regimens using one or more pharmacologic agents.
It seems likely that chronic fatigue will be the dominant chronic health disorder of the next century. Twenty one percent of 500 patients visiting a primary care clinic in Boston (3) and 24% of 1159 patients at two adult care clinics in Texas (4) complained of chronic fatigue. The CDC estimates that there may be 100,000 patients in the United States who suffer from CFS(5). This is clearly a gross underestimation.
The state of chronic fatigue cannot be understood through the current simplistic, single-agent single-disease model. What is required is a holistic "systems study" of man and his environment, including nutritional and fitness status, the impact of microorganisms on human biology, and the stress of modern life. What is needed is an integrated program of fundamental research into human energy dependent mechanisms, and how they are adversely affected by incremental molecular oxidant stress. Recognition and elimination of specific causes of increased oxidant stress, whenever possible, and nutritional and self-regulatory antioxidant techniques remain the primary approach to clinical management of chronic fatigue.
In 1985, the CDC proposed the major and minor criteria for the diagnosis of chronic fatigue syndrome (2). Rigid criteria of this nature are not usable in our model of accelerated oxidative molecular injury, in which there are two important issues:
1. How much fatigue interferes with the patient's life?
2. What is the molecular basis of the fatigue?
The CDC criteria indicate that chronic fatigue syndrome may not be diagnosed when secondary to an existing organic or psychiatric disorder, basically a reductio ad absurdum. It is the essential molecular duality of oxygen, and its impact upon human biology, which is being proposed here as the real culprit(6,7).
Oxidant Stress, Redox Dysregulation and Chronic Fatigue
The life span of an organism is governed by the essential balance between metabolic oxidant stress and antioxidant defense. This is supported by considerable experimental evidence (8-13), indicating the role of oxidant stress and free radicals in pathogenesis of degenerative and immunologic disorders.
Knowledge of basic redox dynamics and free radical pathology is essential for understanding both the aging process and the initiation and progression of disease processes. The redox reaction, as well as determining life span, also determines the rate of metabolism and tissue auto-oxidant. Degenerative and immunologic disorders represent premature and accelerated molecular and tissue aging. Molecular injury and molecular repair are energy dependent. Cellular injury, expressed in morphologic terms, is a late event. Thus, clinical disease in its initial stages might be seen as redox dysregulation. Evidence exists (14) for evolution of mitochondria and other cellular organelles from oxygen using pro-karyote which migrated into protoeukaryotic cells, thus protecting them from oxygen toxicity.
Molecular Defense Pathways
Our concept of chronic illness is facilitated by understanding the balance that must be maintained between oxidant and antioxidant molecules (6,7); oxidants, which accelerate the wear and tear caused by environmental stress, are counter-balanced by antioxidants.
Oxidative metabolism is the first line of defense against environmental attack. Clinical symptoms associated with initial molecular and energy events are vague, hard to define, attributable to multiple organ systems, and often include chronic fatigue. Not unexpectedly, physical examination in patients with chronic fatigue often yields no clues to the cause of chronic fatigue.
Oxygen, though essential to life, is toxic. Cells need it, but they are aged by it. Of this we generally have little understanding in the clinical practice of medicine. Oxidation is a spontaneous process. Reduction requires expenditure of energy. This molecular duality of oxygen represents the economy of nature at its best.
The primary molecular defenses against oxidant tissue damage are mediated by superoxide dismutase, catalase and glutathione peroxidase intracellulary, by plasma proteins and ascorbate extracellularly, and by the lipid soluble antioxidant tocopherol and carotene predominantly in the hydrophobic cell membrane compartment (15, 16). An inverse relationship between plasma levels of certain dietary antioxidants and incidence of cancer has been documented (17). There is some indirect evidence showing inadequate protection of cells by normal levels of plasma antioxidants against DNA damage caused by oxidant overload (18). Increased redox stresses play central roles in the pathogenesis of chronic immune, degenerative, allergic, and chemical sensitivity disorders.
The integrity of plasma membrane and mitrochondrial oxidative enzyme systems is essential for initial electron transfer events that preserve molecular defenses and cellular health. Diseases begin when these initial electron transfer defenses fail as a consequence of oxidant injury. The occurrence of disease in specific organs is determined by the impact of environmental factors upon the genetic make-up of the individual. The oxidative stresses of interest in this context include enzyme induction and inactivation involving the dysregulation of acetylation, methylation, conjugation, glucuronidation, carbon and sulfur oxidation, plasma membrane receptors, membrane peroxidation, oxidative protein cross-linking and molecular permutations of oligo- and polysaccharides caused by oxidative injury.
For example, cysteine oxygenase plays a role in the formation of sulfoxides from S-carboxyl-L-methylcysteine, a reaction which varies widely among individuals (19). Impaired sulfur oxidation has been documented in many autoimmune disorders including primary biliary cirrhosis (20), rheumatoid arthritis (21,22), and systemic lupus erythematosus (23). An inadequate supply of inorganic sulfate limits the rate of formation of non-toxic conjugated sulfates, so this is clinically significant.
Evidently these lines of molecular defenses are ineffective against dioxins, chlordane and other related molecules which have a long half life. Enzymes frequently activated by xenobiotics include cytochrome P-450 systems and enzymes frequently inactivated by them include choline esterases, sulfite oxidases and phenol sulfotransferases.
In chronic fatigue, evidence for enzyme induction as well as inactivation can be developed by the study of their by-products and metabolites of xenobiotics. For example, increased urinary levels of D-glucaric acid indicate induction of hepatic enzyme induction by xenobiotics and some viruses (Pangborn J. Personal Communication). Similarly, mercapturic acid serves as an indicator of the detoxification process that involves oxidant glutathione complex (Pangborn J. Personal Communication). An increased urinary clearance of mercapturic acid has been reported in patients with chronic fatigue. The enzymatic efficiency of sulfite oxidases and enzyme systems involved with trans-sulfuration steps are of special importance to individuals with chronic fatigue associated with IgE mediated disorders such as asthma, autoimmune diseases, and chemical sensitivity and toxicity. These functions can be assessed by measurements of urinary sulfites and sulfates.
Evidence is accumulating that the pathogenic mechanisms of environmental disorders involve complex inter-relationships between exogenous toxins, genes, enzymatic inductions, and structural and functional impairements of immune cells (25,25). toxins can directly bend or disfigure DNA molecules so that they become vulnerable to deletion of transcription by a host of proteins. In health, DNA is usually packed tightly within the nucleus and is hard to reach. When disfigured it becomes more accessible to proteins in its vicinity. Thus injured, DNA may encode specific enzyme systems. The enzyme activation so caused may persist for long periods of time and eventually lead to clinical disorders. This is illustrated by the example of DNA injury caused by dioxins (24,25).
Finally, the classical immunologic mechanisms of Gell and Coombs must be considered. While this classification has been of enormous value in delineating essential mechanisms underlying clinical and morphologic patterns of disease, it sheds little light on molecular events that initiate immunologic injury and lead to chronic fatigue. An exception to this is the case of IgE mediated disorders - clinical states in which the incriminated triggers can be effectively managed with proper diagnostic and therapeutic approaches, in general with excellent clinical responses.
Subcellular and cellular structural changes observed with morphologic studies are late events. Such changes are not relevant to our discussion of the causes of chronic fatigue. In any case, such morphologic changes have not been described in chronic fatigue.
Experimental and Clinical Evidence in Support of the Hypothesis
1. Spontaneity of Oxidation in Nature and Aging
Bjorksten (26) and Harmon et al (8, 13, 27) advanced their theories of protein cross-linking and free radical injury respectively as the basic mechanisms of agin in man. These phenomenons are the result of oxidative molecular injury which may be regarded as the true nature of the aging process (6,7). tissue capacity for anti-oxidant generation provides the counterbalance to spontaneous oxidation. There is a large body of clinical and experimental data to support this (8-13).
2. Increasing Oxidizing Capacity of Earth
It is predicted that tropospheric ozone will decrease by up to 1% per year over the next 50 years (28). Man today faces accelerated oxidative molecular damage much like protoeukaryotes did millions of years ago. It would seem to be a defensible assumption that these rapid increases in oxidant stress of human biology have some pathogenic relationship to the rising incidence of chronic fatigue unassociated with specific clinico-pathologic entities. Reports of vague, poorly defined states of ill health in many veterans of the recent Persian gulf was appear to fit into a category of illness related to high oxidant stress. Whatever criteria is used for the diagnosis of chronic fatigue (2-5), it is evident that the incidence of chronic fatigue in the closing decades of the 20th century far exceeds that reported in the opening decades.
3. Cell Membrane Ionic Channel Gating Proteins, Oxidative Injury and Chronic Fatigue
A cell propagates and integrates electrical signals by means of its membrane channels. Transfer of ions across the channels is regulated by gating proteins with multiple subunits containing voltage sensors. The function of gating proteins is finely orchestrated to attain a high order of subunit cooperation (29,30). Oxidative damage to ion channel proteins in the cell membrane can be expected to increase membrane permeability, leading to efflux of the intracellular ions, magnesium and potassium, and influx into the cell of the extracellular ion, calcium. Strong evidence for this is furnished by clinical studies showing efficacy of calcium channel blockers for a growing number of clinical entities linked to oxyradicals (31). It is also supported by the efficacy of intravenously administered magnesium and potassium for chronic fatigue and many other pathologic states associated with increased oxidative stress(32).
Lowered levels of intracellular ions have been documented in chemically-induced cell membrane injury, chemical sensitivity, food allergy and viral infections. Strong clinical evidence for severe gating derangements at the cell membrane in patients with chronic fatigue is furnished, as we shall see later in this article, by studies with intravenous magnesium and potassium infusions in almost all cases (33).
Human gene encoding specific enzymes can be induced by oxidative injury (34). Evidence that a deletion polymorphism in the gene encoding angiotensin-converting enzyme is a risk factor for myocardial infarction has been recently reported (35,36). Comparative study of epidemiologic data for coronary artery disease the beginning and the end of this century strongly support the possibility of this being caused by oxidant stress. It seems probable from these considerations that deletion polymorphism in the gene encoding oxidative and detoxification enzymes will be found in time in patients with chronic fatigue.
4. Immunologic Abnormalities in Chronic Fatigue
A very large number of immunologic abnormalities have been described in chronic fatigue states. These include depression of cell mediated immunity, phenotypic and functional deficiencies of natural killer cells, and diminished ability of mutagenically stimulated mononuclear cells, thought to represent cellular exhaustion (37,88). Variable changes in CD4 and CD8 lymphocytes have been reported, including depletion of CD4 and CD45RA cells, and alterations in humoral responses such as mild IgA deficiency and elevated levels of immune complexes. Other reported abnormalities include the presence of autoantibodies such as rheumatoid factor, antinuclear antibodies and cold agglutinins, and increased B cells (39-44). Evidence of T-cell activation is furnished by studies showing elevated blood levels of IL-2 and T8 receptors and increased numbers of CD3 and CD20 and and CD56 cells (44). Blood levels of both 2'5'. A synthetase and RNAase are elevated, indicating activation of lymphocytes by viruses or exposure to interferon (40). These changes appear to represent polyclonal B-cell activation. These observations have led investigators to consider CFS as an acquired immunodeficiency state caused by one or more viruses belonging to the Herpes or enterovirus families. Indeed, in a very small subset of patients, strong circumstantial evidence suggests an important initial role of viral infections. In the hypothesis proposed here, these immunologic aberrations are regarded as consequences of accelerated oxidative molecular injury rather than primary cause of chronic fatigue.
5. Association of HLA-DR3 Antigens with CFS and with Some Autoimmune Disorders
The association of several autoimmune disorders with HLA-DR4 region antigens is well established (44). It has been reported that 46% of a group of patients with chronic fatigue were positive for antigens of HLA-DR3 egion (45). This suggests a genetic predisposition for individuals with these HLA antigens or autoimmune injury and development of autoimmune syndromes. Can chronic fatigue be considered as a part of the spectrum of autoimmune response? Patients with chronic fatigue show clear evidence of autoimmune injury (37-42). It has already been pointed out that abnormal autoimnune responses are associated with, and most likely triggered by, induction of inactivation of certain enzyme systems by oxidative injury (19-23, Pangborn J. Personal Communication). These lines of evidence lend support to the proposed hypothesis, and further suggest that oxidative injury to certain enzyme systems may be the molecular pathogenetic mechanism involved in immunologic drangements observed in chronic fatigue.
6. Morphologic Evidence for Accelerated Oxidant Stress on Cell Membrane.
Morphologic abnormalities of cell membranes have been observed with high-resolution, phase contrast microscopy, in 50-80% of erythrocytes in patients with persistent chronic fatigue (46). Abnormalities included crenation, sharp angulation, spike formation and rigidity, most accentuated during acute exacerbations of fatigue during acute and subacute allergic reactions. Studies repeated 15 minutes after infusion of 15 grams of ascorbic acid showed reversal of the membrane abnormalities in over 80% of the previously affected cells.
7. Galvanic Skin Responses and Electromyopotentials in Chronic Fatigue
A consistent pattern of markedly diminished galvanic skin responses and increased electromyopotentials is observed in patients with chronic fatigue as compared with healthy subjects and patients with essential hypertension (Ali M. Unpublished observations). Diminished perfusion and decreased glucose utilization in certain parts of the limbic system have been reported in patients with chronic fatigue (47). This is consistent with the consequences of oxidative injury to neurons. During training sessions in effective self-regulatory methods, many patients with chronic fatigue show moderate to marked reductions in electromyopotentials for short periods of time. With long-term training in slow, sustained breathing patterns with prolonged unforced expiration, reduction in muscle potentials is achieved by most of them.
8. Viral and Other Infections Associated with CFS
The cause of chronic fatigue has been considered to be chronic. Epstein-Barr infections (48-51). Recent laboratory evidence has pointed to retroviral sequences (52). Occurrence of viral infections does not necessarily indicate that they are causative. They have been shown to increase oxidative stress, and mortality from acute influenza infection in mice can be drastically reduced with the use of superoxide dismutase (53). Viral infections do not lead to chronic persistent fatigue when they are managed with aggressive oral and intravenous antioxidant therapies and other necessary supportive measures (Ali, M. Unpublished observations). Apparently, viral infections lead to chronic fatigue only in states of suppressed molecular defenses caused by food allergy, extensive use of antibiotics, stress, anxiety and depressed states. They appear to be the proverbial straw to break the camel's back of molecular defenses.
Recently, several cases of chronic fatigue syndrome have been shown to meet the diagnostic criteria of idiopathic CD-4 T-lymphocytopenia (ICL), commonly known as AIDS-like illness in HIV negative individuals (54). Serologic evidence of past Epstein-Barr virus infection was seen in about two thirds of a group of patients and about one third had very high titers of IgG antibodies, presumably reflecting ongoing viral replication. One patient with long standing chronic fatigue showed serologic evidence of HTLV-III infection. She responded well to nutrient therapy and obtained near-complete relief within 8 weeks (Ali, M. Unpublished observations).
9. IgE-Mediated Allergy in Chronic Fatigue
We investigated the prevalence of IgE antibodies with specificity for 8 molds, 12 pollens, 6 foods, and cat an dog epithelial antigens in one hundred consecutive patients with the clinical picture o CFS of more than six months duration. Micro-elisa assays for allergen-specific IgE antibodies were performed with a previously described method (55). Ninety-eight gave a history of past or present allergy symptoms. IgE antibodies with specificity for three or more molds were detected in all cases. Prevalence of IgE antibodies with specificity for pollen of grasses, trees and weeds ranged from 62% to 78%, and those for foods from 84% to 83%.
10. Chemical Sensitivity and Toxicity
Chemical Toxicity is largely a dose-dependent phenomenon, and chronic fatigue associated with exposure to industrial toxins is well established (56). Chemical Sensitivity, by contrast, is dose independent. Chronic fatigue associated with its clinically well recognized, though the pathogenesis has not been fully recognized, though the pathogenesis has not been fully elucidated. Both chemical toxicity and sensitivity clearly result from oxidizing potential of these agents, as already discussed.
11. Metabolic Derangements
Metabolic immunodepression resulting in impairment of cell mediated immunity and a phagocytic dysfunction of macrophages has been proposed as a major contributory cause of the chronic fatigue syndrome(57). Factors that lead to immunosuppression include disturbances of carbohydrate and lipid metabolism, proposed by Dilman. These include glucose intolerance, post-prandial hyperinsulinemia, raised serum levels of free fatty acids and LDL cholesterol and accumulation of oxidized lipids in the plasma membranes of T-lymphocytes and monocytes. Many clinicians recognize chronic fatigue as an important aspect of the clinical syndrome of rapid hyperglycemic-hypoglycemic shift that are followed by similar peaks of insulin and adrenaline. Catecholamines are powerful oxidizing agents (58). Glucose autoxidation causes oxidative protein damage in the experimental glycation model and diabetes mellitus and aging(59). Both factors support the proposed hypothesis.
12. Anemia, Mercury Toxicity and Chronic Fatigue
Fatigue is a well recognized symptom of anemia, and is considered as a consequence of lowered oxygen carrying capacity of blood. However, anemia as a major or as a contributory cause of fatigue was not observed in a single case of 100 consecutive cases of chronic fatigue cited above. Diminished blood levels of oxyhemoglobin were observed in a majority of patients with mercury toxicity and chronic fatigue and a lack of oxygen was proposed as a possible molecular basis of chronic fatigue(60). This observation is consistent with the proposed hypothesis. Mercury and other heavy metals are known to bind with the reducing potential and /or with the reducing function such as the sulfhydryl group of enzymes and other proteins, thereby inactivating them(56). As a consequence of this, the natural reducing mechanisms are impaired and oxidative mechanisms potentiated. Indeed, this mechanism is likely to playa role in the etiology of chronic fatigue in patients with heavy metal overload in the study cited above.
13. Clinical Evidence: Efficacy of Intravenous Anti-Oxidant Nutrient Therapy
Strong clinical evidence of the hypothesis is furnished by studies demonstrating the efficacy of oral and intravenous anti-oxidant nutrient therapies(33). Of 100 consecutive patients with the chief complaint of chronic fatigue who were treated at the Chronic Fatigue Clinic at the Institute, 46 met the CDC criteria for chronic fatigue syndrome. IgE antibodies with specificity for at least three mold antigens were present in all 100 patients. Eighty eight patients gave a history of extensive antibiotic therapy and symptoms indicative of altered states of bowel ecology. Elevated blood levels of one or more heavy metals (Pb, Hg, Al, Cd and As) were found in 37 patients. Serologic evidence for active viral replication was not detected in the majority of patients. Major stress (as assessed by the patient) preceded the onset of chronic fatigue is less than 10% of patients. All patients were managed with integrated treatment protocols of oral and intravenous nutrient therapies, antigen immunotherapy for IgE mediated allergy, training in effective methods for self-regulation and a program for slow, sustained exercise. The intravenous nutrient protocol was formulated to provide a strong nutrient anti-oxidant support, and not to correct any putative nutritional deficiencies. The outcome data for these 100 patients with chronic fatigue were as follows: Excellent response (symptom relief >80%), 68%; good response (symptom relief between 60% and 80%), 12%; modest response (symptom relief between 40% and 60%); and poor response (symptom relief between 0 and 40%), 12%.
Chronic fatigue is emerging as the most dominant health disorder of our time. It is proposed that the state of chronic fatigue is the result of accelerated oxidative molecular injury caused by the impact upon our genetic make-up of environmental, nutritional, microbiological and stress-related factors. This model of molecular-energetic-basis of fatigue is useful for designing successful, nondrug therapies to reduce oxidative molecular stress and relieve chronic fatigue.