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Reprinted form the Journal of Advancement in
Medicine, Volume 6, Number 2, Summer 1993
Hypothesis: Chronic Fatigue is a State of
Accelerated Oxidative Molecular Injury
Majid Ali, M.D.
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.
INTRODUCTION
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.
Diagnostic Criteria
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.
Molecular Defenses
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%.
Conclusion
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.
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