Glutathione Depletion-Methylation Cycle Block:
A Hypothesis For the Pathogenesis of Chronic Fatigue Syndrome
by Richard A. Van Konynenbury Ph.D.
Independent Researcher and Consultant, (richvank@aol.com)
INTRODUCTION AND HYPOTHESIS.
At the Seventh International Conference of the AACFS in 2004, the author
proposed and defended the hypothesis that glutathione depletion is an important
part of the pathogenesis of CFS (1).
In the conclusions of that paper it was noted that it seemed likely that
there are vicious circle mechanisms involved in CFS that prevent glutathione
repletion from being the complete answer for treating this disorder.
Recent autism research (2,3) suggests that in that disorder a vicious circle
involving the methylation cycle apparently chronically holds down the level of
glutathione.
The present author has recently proposed (4) that this same mechanism is
active in many cases of CFS. This model for CFS will be referred to as the
Glutathione Depletion—Methylation Cycle Block (GD-MCB) Hypothesis.
This mechanism appears to be capable of explaining and drawing together
numerous features of CFS that have been reported in the peer-reviewed
literature.
What is the methylation cycle and what does it do?
The methylation cycle (also called the methionine cycle) (5) is a major part
of the biochemistry of sulfur and of methyl (CH3) groups in the body. It is also
tightly linked to folate metabolism and is one of the two biochemical processes
in the human body that require vitamin B12 (the other being the methylmalonate
pathway, which enables use of certain amino acids to provide energy to the
cells).
This cycle supplies methyl groups for a large number of methylation
reactions, including those that methylate (and thus silence) DNA (6), and those
involved in the synthesis of a wide variety of substances, including creatine
(7), choline (7), carnitine (8), coenzyme Q-10 (9), melatonin (10), and myelin
basic protein (11). Methylation is also used to metabolize the catecholamines
dopamine, norepinephrine and epinephrine (12), to inactivate histamine (13), and
to methylate phospholipids (14), promoting transmission of signals through
membranes.
The role of the methylation cycle in the sulfur metabolism is to supply
sulfur-containing metabolites to form a variety of important substances,
including cysteine, glutathione, taurine and sulfate, via its connection with
the transsulfuration pathway (5).
This cycle balances the demands for methylation and for control of oxidative
stress (15)
How is the methylation cycle dysfunctional in autism, and how
is this related to glutathione depletion?
In autism the methylation cycle was found by James et al. (2,3) to be blocked
at methionine synthase, which is the step involving methylation of homocysteine
to form methionine (see diagram).
Two effects of this block that they measured are a significant decrease in
the level of plasma methionine and lowering of the ratio of S-adenosylmethionine
to S-adenosylhomocysteine. The latter causes a decreased capacity for promoting
methylation reactions (16).
In addition, they found (2,3) that the flow through the transsulfuration
pathway (see diagram) was also decreased, resulting in lower plasma levels of
cysteine and glutathione and a lowered ratio of reduced to oxidized glutathione,
all of which they measured. This lowered ratio reflects a state of oxidative
stress (17).
The block in the methylation cycle and the glutathione problem were found to
be linked, since supplements used to restore the methylation cycle to normal
operation (methylcobalamin, folinic acid and trimethylglycine) also restored the
levels of reduced and oxidized glutathione (2).
Do genetic factors contribute to producing this methylation
cycle dysfunction in autism?
It is known from studies of twins that genetics plays an important
predisposing role in autism (18). The fact that the rate of incidence of autism
has increased dramatically in recent years is evidence that there is also an
important environmental component in the development of cases of autism (3),
since the population’s genetic inheritance is relatively constant over much
longer periods.
James et al. (3) found that there are measurable genetic differences between
children with autism and healthy controls. The differences they measured are
associated with genes that encode enzymes and other proteins impacting the
methylation cycle, the folate metabolism and the glutathione system.
In particular they found differences in allele frequency and/or significant
gene-gene interactions for genes encoding the reduced folate carrier (RFC),
transcobalamin II (TCN2), catechol-O-methyltransferase (COMT),
methylenetetrahydrofolate reductase (MTHFR), and one of the glutathione
transferases (GST M1).
These genetic results, combined with the biochemical observations of
dysfunction in the methylation cycle, strongly suggest that variations in genes
associated with this cycle and its related biochemistry are involved in the
genetic predisposition to developing autism.
What evidence suggests that this same dysfunction and similar
genetic factors are also present in chronic fatigue syndrome?
1. Methionine concentrations are reported to be below normal in both plasma
(19) and urine (20) in CFS patients. Low methionine can be caused by a
methylation cycle block.
2. Four magnetic resonance spectroscopy studies in CFS (21-24) have found
elevated choline-to-creatine ratios in various parts of the brain. Both choline
and creatine arise partly from the diet and partly from synthesis in the body.
Since the syntheses of these two substances are the main users of methylation
(7), a methylation deficit would be expected to decrease the rate of synthesis
of both of them, and hence to decrease their levels in the cells. When this
occurred, it would be unlikely that their ratio would remain the same, since the
fractions of each supplied by synthesis would not likely be the same, nor would
the decrease in rates of synthesis of these two substances likely to be
proportional to their levels in the cells. Since creatine synthesis is the
greater user of methylation (7), it might be expected that the choline-to-creatine
ratio would increase, as is observed. It therefore appears that a methylation
cycle block could explain this well-replicated observation in CFS.
What evidence suggests that this same dysfunction is also
present in chronic fatigue syndrome? (continued)
3. Some substances that require methylation for their biosynthesis have been
found to be at below-normal levels in CFS patients, and/or patients have been
found to benefit by supplementing them. This has been reported in eleven of the
studies in CFS of carnitine, beginning with the work of Kuratsune et al.
(25-34), both the studies of coenzyme Q10 (35, 36), a study that included
choline as phosphatidylcholine in a combination supplement (37), and one recent
study of melatonin (38) (though it should be mentioned that earlier studies of
melatonin in CFS found normal or elevated levels, and/or did not find benefit
from supplementation (see review in ref. 39), suggesting that other issues in
addition to the methylation deficit might be involved in the case of melatonin.
See "Magnesium depletion" later in this paper).
4. Vitamin B12, which plays a key role in the methylation cycle and was one
of the supplements used to restore this cycle in the autism work (2), has a long
history (39,40) as one of the most helpful of the essential nutrients in CFS
when given in high-dosage injections. Lapp and Cheney (41, 42) found that in
urine organic acids testing of 100 CFS patients, 33% had elevated homocysteine,
38% had elevated methylmalonate, and 13% had both (29,30). The elevated
homocysteine implicates the methylation cycle,
What evidence suggests that this same dysfunction is also
present in chronic fatigue syndrome? (continued)
while the elevated methylmalonate indicates that the other pathway that
requires vitamin B12 showed deficiency as well. Lapp and Cheney (42) found that
50 to 80% of over 2,000 patients reported benefit from high-dose vitamin B12
injections. Evengard et al. (43) reported that vitamin B12 levels in the
cerebrospinal fluid of 10 of 16 CFS patients were below their detection limit of
3.7 pmol/L. Regland et al. (44) found both low vitamin B12 (in 10 out of 12
patients) and high homocysteine (in all 12 patients studied) in the
cerebrospinal fluid of CFS patients. There were significant correlations between
these parameters and symptoms.
Regland et al. (45) performed an open trial in which they gave 1,000
microgram weekly injections of hydroxocobalamin for at least 3 months to the 10
female patients from this study who had both low B12 and elevated homocysteine.
They found that the treatment was significantly more beneficial if the patient
did not have the thermolabile allele of the polymorphic gene for MTHFR. They
concluded that vitamin B12 deficiency was probably contributing to the increased
homocysteine levels. They also found that the effect of vitamin B12
supplementation was dependent on whether the available methyl groups were
further deprived by the existence of thermolabile MTHFR. This work implicated
the methylation cycle in
What evidence suggests that this same dysfunction is also
present in chronic fatigue syndrome? (continued)
the pathogenesis of CFS, and it also pointed to the importance of a genetic
component, involving one of the same genes that have been implicated in autism
(3).
5. Folinic acid was recently found to produce subjective improvement in
symptoms in 81% of 58 CFS patients tested (46). This was also one of the
supplements used to restore the methylation cycle in the autism research (2).
6. Many studies have reported evidence for oxidative stress in CFS (47-61).
7. There have been several reports of depletion of reduced glutathione in at
least a substantial subset of CFS patients (49-51, 53,54,59,62). Reduced
glutathione augmentation is now widely used by CFS clinicians, who have found
that augmenting glutathione by various means has been helpful to many of their
patients (49,50,63-65).
8. Polymorphisms in the gene coding for the COMT enzyme were found by
Goertzel et al. (66) to be some of the most important of those examined for
distinguishing CFS cases from controls. As noted earlier, COMT is a
methyltransferase, associated with the methylation cycle. In autism, the COMT
472G>A polymorphism showed significant difference between cases and controls
(3).
If this same dysfunction is present in both autism and CFS,
how can the obvious differences between these two disorders be explained?
Major differences are seen in the gender ratio and in the symptoms of these
two disorders.
Autism is found primarily in boys, at a ratio of about 4 to1 (boys to girls)
(67), while CFS occurs mainly in adult women at a ratio measured at 1.8 to 1
(women to men) by Jason et al. (68) in one large epidemiological study and 4.5
to 1 (women to men) by Reyes et al. (69) in another.
The most striking symptoms in autism involve the brain and are very
characteristic of this disorder. They are described as follows by the Diagnostic
and Statistical Manual of Mental Disorders (70):
1. Qualitative impairment in social interaction, as manifested
by at least two of the following:
a. Marked impairment in the use of multiple nonverbal behaviors such as
eye-to-eye gaze, facial expression, body postures, and gestures to regulate
social interaction.
b. Failure to develop peer relationships appropriate to developmental level.
c. A lack of spontaneous seeking to share enjoyment, interests, or achievements
with other people (e.g., by a lack of showing, bringing, or pointing out objects
of interest).
d. Lack of social or emotional reciprocity.
2. Qualitative impairments in communication as manifested by
at least one of the following:
a. Delay in, or total lack of, the development of spoken language (not
accompanied by an attempt to compensate through alternative modes of
communication such as gestures or mime).
b. In individuals with adequate speech, marked impairments in the ability to
initiate or sustain a conversation with others.
c. Stereotyped and repetitive use of language or idiosyncratic language.
d. Lack of varied, spontaneous make-believe play or social imitative play
appropriate to developmental level.
If this same dysfunction is present in both autism and CFS,
how can the obvious differences between these two disorders be explained?
(continued)
3. Restricted repetitive and stereotyped
patterns of behavior, interests, and activities, as manifested by at least one
of the following:
a. Encompassing preoccupation with one or more stereotypic and restricted
patterns of interest that is abnormal either in intensity or focus.
b. Apparently inflexible adherence to specific, nonfunctional routines or
rituals.
c. Stereotypic and repetitive motor mannerisms (e.g., hand or finger flapping or
twisting, or complex whole-body movements).
d. Persistent preoccupation with parts of objects.
CFS involves a large variety of symptoms (71,72), the chief ones being
extreme fatigue, post-exertional malaise and/or fatigue, sleep dysfunction,
muscle pain, and symptoms involving the brain that are significant but less
profound than in autism (e.g. cognitive and memory difficulties).
The author proposes that these differences result at least in part from the
different ages at onset. Autism develops early in life, before the brain is
completely developed and before puberty, while the onset of CFS occurs after
brain development is completed and (for the most part) after puberty.
Pangborn (73) has discussed five hypotheses that have been suggested to
explain the higher prevalence of autism in boys. Of these, the one that appears
to be most consistent with the present author’s hypothesis of a common
pathogenesis between CFS and autism is the one put forward by Geier and Geier
(74). Their hypothesis proposes
If this same dysfunction is present in both autism and CFS,
how can the obvious differences between these two disorders be explained?
(continued)
that the higher prevalence of autism in boys results from the potentiation of
mercury toxicity by testosterone, while estrogen is protective. There is
increasing evidence that mercury was a significant factor in the etiology of
many cases of autism, because mercury-containing thimerosol was used as a
preservative in vaccines given to them. Since thimerosol was removed from
childhood vaccines, the number of new cases of neurodevelopmental disorders,
including autism, has been found to be dropping (75).
The present author has proposed a hypothesis (76) to explain the higher
prevalence of CFS in women, involving an additional bias toward oxidative stress
due to redox cycling in the metabolism of estradiol when certain polymorphisms
are present.
With regard to symptoms, it seems likely that the role of methylation in the
formation of myelin basic protein (77) is at least part of the explanation for
the major problems in brain development in autism and the symptoms that result
from them.
Fatigue is not recognized to be a major feature of autism. However, it should
be noted that the evaluation of fatigue is usually based on self-report, which
is not possible in children who are unable to speak. Also, it seems possible
If this same dysfunction is present in both autism and CFS,
how can the obvious differences between these two disorders be explained?
(continued)
that fatigue may be manifested differently in very young children as compared
with adults. Features such as hyperactivity and irritability may reflect fatigue
in these patients.
Chronic pain may also be difficult to identify and characterize in children
who do not have speech. A recent paper suggests that chronic pain may be the
initial presenting symptom in cases of undiagnosed autism (78).
Many of the other phenomena found in CFS are also found in autism, but
historically they have not received as much attention in autism as the
brain-related symptoms, perhaps because the latter are so striking and profound.
Some of the other phenomena that autism has in common with CFS in addition to
those already mentioned are elevated proinflammatory cytokines (79), Th2 shift
in the immune response (80), low natural killer cell activity (81),
mitochondrial dysfunction (82, 83), carnitine deficiency (83),
hypothalamus-pituitary-adrenal (HPA) axis dysfunction (84), gut problems (85),
and sleep problems (86).
How does the Glutathione Depletion—Methylation Cycle Block (GD-MCB)
Hypothesis explain other aspects of chronic fatigue syndrome?
Etiology: According to the GD-MCB Hypothesis, CFS is caused by a
combination of two factors:
(1) a genetic predisposition (87), which is currently only partly known, and
(2) some combination of a variety of physical, chemical, biological and/or
psychological/emotional stressors, the particular combination differing from one
case to another (See Ref. 1 for a review.).
So far, polymorphisms in genes coding for the following proteins have been
found to be associated with CFS in general or with a subset:
(1) Serotonin transporter (5-HTT) gene promoter (88)
(2) Corticosteroid binding globulin (CBG) (89)
(3) Tumor necrosis factor (TNF) (90)
(4) Interferon gamma (IFN-gamma) (90)
(4) Proopiomelanocortin (POMC) (91)
(5) Nuclear receptor subfamily 3, group C, member 1, glucocorticoid
receptor (66,91)
(6) Monoamine oxidase A (MAO A) (91)
(7) Monoamine oxidase B (MAO B) (91)
(8) Tryptophan hydroxylase 2 (TPH2) (66,91)
(9) Catechol-O-methyltransferase (COMT) (66)
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome?
In addition, a COMT polymorphism has reported to be associated with
fibromyalgia (92, 93), and polymorphisms in the genes for the detoxication
enzymes CYP2D6 (cytochrome P450 2D6) and NAT2 (N-acetyl transferase 2) have been
found to be associated with multiple chemical sensitivities (94). These may be
relevant to CFS because of its high comorbidities with these two disorders.
All these proteins touch on the pathogenesis mechanism described in this
paper, which is what would be expected if this Hypothesis is valid.
With regard to the stressors found to precede onset of CFS, they are known to
raise cortisol secretion (prior to onset and early in the course of the
illness), to raise epinephrine secretion and to place demands on glutathione,
leading to oxidative stress (1).
According to this Hypothesis, when reduced glutathione is sufficiently
depleted and the oxidative stress therefore becomes sufficiently severe in a
person having the appropriate genetic predisposition, a block is established at
methionine synthase in the methylation cycle (95,2,3). Because the methylation
cycle is located upstream of cysteine and glutathione in the sulfur metabolism,
these are further depleted, and a vicious circle is formed.
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome?
Note that infectious pathogens are included among the possible biological
stressors that can contribute to the onset of CFS. In particular, Borrelia
burgdorferi, the bacterium responsible for Lyme disease, has been found to
deplete glutathione in its host (96). This may explain the very similar
pathophysiologies of chronic Lyme disease and CFS. This may also explain the
epidemic clusters of CFS, which seem to have been produced by a virulent
infectious pathogen (or pathogens). Perhaps the genetic factors are less
important in producing the onset if a very virulent pathogen is present.
Epidemiology: According to the GD-MCB Hypothesis, the prevalence of CFS
is determined by the frequency in the population of the combined presence of
certain genetic polymorphisms (yet to be completely identified) and of the above
described stressors occurring coincidentally in those having the polymorphisms.
As noted earlier, the author has proposed that the higher prevalence in women is
a result of increased bias toward oxidative stress, resulting from redox cycling
in the metabolism of estradiol when certain polymorphisms in detoxication
enzymes are present (76).
Suppression of parts of the immune response: Elevation of cortisol due to
long-term stressors causes a suppression of the cell-mediated immune response
and a shift to Th2 (97).
How does the GD-MCB hypothesis explain other aspects of
chronic fatigue syndrome?
Depletion of reduced glutathione likewise causes a shift to Th2 (98, 99).
The elevation of cortisol prior to onset and in the early course of the
illness also (temporarily) suppresses inflammation (100).
The cytotoxicity of natural killer (NK) cells and CD8 T cells in CFS has been
found to be low, and Maher et al. found this to be associated with a deficiency
of perforin secretion (101). According to the GD-MCB Hypothesis, in CFS perforin
secretion is inhibited by depletion of reduced glutathione because glutathione
is needed to form the disulfide bonds in their proper configurations in
secretory proteins (102). Depletion of glutathione therefore causes misfolding
and recycle of perforin molecules, which have twenty cysteine residues and thus
ten disulfide bonds (103). This misfolding mechanism would affect other
secretory proteins in CFS that are synthesized in cells having glutathione
depletion as well, which may account for the observation of misfolded proteins
in the spinal fluid of CFS patients by Baraniuk et al. (104).
Proliferation of T lymphocytes is inhibited by the block in the folate cycle,
which inhibits production of new RNA and DNA (105).
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome?
Viral and intracellular bacterial reactivation:
According to the GD-MCB Hypothesis, depletion of reduced glutathione is the
trigger for the reactivation of latent viral and intracellular bacteria in CFS.
The infections found initially in a case of CFS are usually due to those
pathogens that are capable of residing in the body in the latent state,
suggesting that these infections arise by reactivation (106). In general,
intracellular glutathione depletion is associated with the activation of several
types of viruses (1, 107-111) as well as Chlamydia (112), and it may account for
reactivation of other latent intracellular bacteria as well. In herpes simplex
type 1 viral infection, raising the glutathione concentration inhibits viral
replication by blocking the formation of disulfide bonds in glycoprotein B
(111). Since glycoprotein B appears to be present in all herpes virus types
(113), it is likely that glutathione depletion is responsible for reactivation
of Epstein-Barr virus, cytomegalovirus and HHV-6 in CFS.
The Coxsackie B3 virus genome is known to code for glutathione peroxidase, a
selenium-containing enzyme (114). Taylor has suggested (115) that such viruses
suppress the immune system of the host by depleting its selenium, thus
inhibiting the host’s use of glutathione peroxidase. Since glutathione
peroxidase makes use of
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome?
glutathione, depletion of reduced glutathione itself would therefore assist
this virus in its mechanism of infection.
Populations more deficient in selenium would be expected to be more
vulnerable to Coxsackie B3 infection. It is interesting to note that nearly all
the studies of Coxsackie virus in CFS have come from the UK. The population
there has become more deficient in selenium since the 1970s, when major sources
of grain in the diet were changed to areas with selenium-deficient soils (116).
Immune activation: This occurs when the immune system detects the
reactivation of pathogens (117).
Activation of 2-5A, RNase-L pathway (118): This pathway is activated by
interferon and double stranded RNA as part of the cellular response to viral
reactivation. According to the GD-MCB Hypothesis, RNase-L remains activated in
CFS because of the suppression of the cell-mediated immune response and the
consequent failure to defeat the viral infection (See "Suppression of parts of
the immune response," above.)
Mitochondrial dysfunction and the onset of physical fatigue: As
hypothesized by Bounous and Molson (119), competition between the oxidative
skeletal muscle cells and
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome?
the immune system for the decreased supply of glutathione and cysteine causes
depletion of reduced glutathione in the skeletal muscles. According to the
GD-MCB Hypothesis, this inhibits the glutathione peroxidase reaction and allows
hydrogen peroxide to build up. This in turn probably exerts product inhibition
on the superoxide dismutase reaction, which allows superoxide, produced as part
of normal oxidative metabolism, to rise in the mitochondria of the oxidative
skeletal muscle cells. Superoxide reacts with nitric oxide to produce
peroxynitrite, as Pall (120) has pointed out. Superoxide also interacts with
aconitase in the Krebs cycle to inhibit it (121), and peroxynitrite can cause
partial blockades in the Krebs cycle and also the respiratory chain (120, 122).
These reactions lower the rate of production of ATP, and this constitutes
mitochondrial dysfunction. Since ATP is needed to power muscle contraction, lack
of it produces physical fatigue.
RNase-L cleavage, leading to formation of the low molecular weight version
(123): Depletion of reduced glutathione removes inhibition of the activity
of calpain (124), which is located in the cytosol with RNase-L, and calpain
cleaves RNase-L (125). (Elastase, the other enzyme found by Englebienne et al.
(125) to be able to cleave RNase-L in the laboratory, is confined to granules
and vesicles inside living cells (126), and thus is not in contact with
RNase-L.)
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome?
Failure to defeat viral and intracellular bacterial infections and continuing
immune activation: According to the GD-MCB Hypothesis, these occur because
of depletion of reduced glutathione (127) and also because the folate metabolism
block prevents production of new DNA and RNA for proliferation of T lymphocytes
(105).
Depletion of magnesium: There is a long history showing depletion of
magnesium in CFS and benefits of supplementation, both orally and by injection
(See review in Ref. 39). Magnesium depletion may be responsible for a variety of
symptoms that are found in CFS (128), including mitochondrial dysfunction,
muscle twitching, muscle pain, sleep problems and cardiac arrhythmia. In
connection with sleep problems, Durlach et al. have found that magnesium
depletion is associated with abnormalities in the level of melatonin and
dysregulation of biorhythms (129). Manuel y Keenoy et al. (54) found that the
subset of CFS patients that was resistant to repletion of magnesium in their
clinical study also showed glutathione depletion. It has also been found that
glutathione depletion causes magnesium depletion in red blood cells (130).
According to the GD-MCB Hypothesis, the depletion of intracellular magnesium in
CFS is another result of depletion of reduced glutathione.
Buildup of toxins: Glutathione depletion allows toxins, including heavy
metals, to build up, because there is not
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome? (continued)
enough glutathione to conjugate these toxins as rapidly as they enter the
body. Mercury is of particular concern, because the population in general has
considerable exposure to it from dental amalgams, fish consumption, and
environmental sources such as nearby coal-fired power plants. There is
considerable clinical experience of mercury buildup in CFS patients (1). Immune
testing has also shown evidence that the immune system has responded to elevated
mercury in CFS patients (131-133).
Solidification of the vicious circle: After the vicious circle has
developed involving the methylation cycle block and the depletion of
glutathione, another factor must come into play to lock in this situation
chronically. It seems likely that buildup of toxins is the factor responsible
for this, by blocking the formation of methylcobalamin and thus the activity of
methionine synthase. It has been shown that one of the important roles of
glutathione normally is to protect the very much smaller (by six orders of
magnitude) concentrations of cobalamins from reaction with toxins by forming
glutathionylcobalamin (134). Without this protection, cobalamins are vulnerable
to reaction with a variety of toxins. An example is mercury. It has been found
that very small concentrations of mercury are required to block the methionine
synthase reaction (135). Because of this additional factor, attempts simply to
correct the glutathione depletion and the oxidative stress after the
How does the GD-MCB Hypothesis explain other aspects of chronic fatigue
syndrome? (continued)
cobalamins have reacted with toxins in most cases will not restore normal
function of the methylation cycle (1).
Neurotransmitter dysfunction: The production of melatonin from serotonin
as well as the metabolism of the catecholamines require methylation, as noted
earlier, and according to the GD-MCB Hypothesis, they are inhibited because of
the decreased methylation capacity. Also, genetic polymorphisms involving
enzymes in the neurotransmitter system have been found to be more frequent in at
least some subsets of CFS patients, as noted earlier. These factors cause
dysfunction of the neurotransmitters.
Further development of mitochondrial dysfunction: As the course of the
illness progresses, it is likely that other factors that result from glutathione
depletion and the methylation cycle block come into play and further suppress
the operation of the mitochondria. These include the buildup of toxins and
infections, depletion of magnesium, and damage to the phospholipid membranes of
the mitochondria by oxidizing free radicals (136). Because the essential fatty
acids in these membranes are polyunsaturated, they are the most vulnerable to
oxidation (137), and they become depleted, at least in some CFS patients (See
review in Ref. 39).
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome? (continued)
HPA axis blunting (138):
According to this
Hypothesis, glutathione depletion in the pituitary gland inhibits production of
proopiomelanocortin (POMC) (which has
two disulfide bonds in its N-terminal fragment (139)), and hence secretion of
ACTH (which is part of POMC), by the same mechanism as inhibition of perforin
synthesis (102) (See "Suppression of parts of the immune response," above.).
This results in the lowering of cortisol secretion by the adrenal glands, which
is a late finding in the course of the illness (140). As noted earlier, genetic
polymorphisms in POMC may also be involved in a subset of CFS patients (91).
Diabetes insipidus (excessive urination, thirst, decrease in blood
volume): According to this Hypothesis, glutathione depletion inhibits production
of arginine vasopressin (141), which has one disulfide bond (142), by the same
biochemical mechanism by which it inhibits perforin and ACTH synthesis (102). It
is likely that the secretion of oxytocin, which also has one disulfide bond and
is also synthesized in the hypothalamus, is also inhibited. Measurements of
oxytocin in CFS have not been reported, but there is evidence that it is low in
some fibromyalgia patients (143), which may be relevant because of the high
comorbidity of CFS and fibromyalgia. A clinician has reported benefit from
oxytocin injections in fibromyalgia patients (144).
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome? (continued)
Low cardiac output (145): According to this Hypothesis, this occurs
because depletion of reduced glutathione in the heart muscle cells lowers the
rate of production of ATP, as in the skeletal muscle cells. This produces
diastolic dysfunction as observed by Cheney (146, 147). Both low blood volume
(see Diabetes insipidus, above), which produces low venous return, and
diastolic dysfunction, which decreases filling of the left ventricle, produce
low cardiac output. In addition, in some cases, as observed by Lerner et al.,
viral infections produce cardiomyopathy (148). According to the GD-MCB
Hypothesis, this is a result of depletion of reduced glutathione and suppression
of cell-mediated immunity. This is another factor that can decrease cardiac
output in CFS.
Orthostatic hypotension and orthostatic tachycardia (149): According to
this Hypothesis, these occur because of low blood volume, low cardiac output and
HPA axis blunting (See Diabetes insipidus, Low cardiac output, and
HPA axis blunting, above.).
Loss of temperature regulation: As pointed out by Cheney (146), this
occurs because of low cardiac output (see Low cardiac output, above),
which causes the autonomic nervous system to decrease blood flow to the skin.
This removes the ability to regulate the rate of heat loss from the skin.
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome? (continued)
Hashimoto’s thyroiditis (150) and elevated incidence of thyroid cancer (151):
According to this Hypothesis, Hashimoto’s thyroiditis occurs in CFS because
depletion of reduced glutathione in the thyroid gland allows damage to
thyroglobulin by hydrogen peroxide, as proposed by Duthoit et al. (152). In
addition, hydrogen peroxide damage to DNA in the thyroid gland may be
responsible for the elevated incidence of cancer there. Hydrogen peroxide is
produced normally by the thyroid to oxidize iodide in the process of making
thyroid hormones (153).
Increasing variety of infections (154) and inflammation (155): According
to this Hypothesis, viral, intracellular bacterial and fungal infections
accumulate over time because the cell-mediated immune response is dysfunctional
(See "Suppression of parts of the immune response," above.). Inflammation
becomes more severe because of the decreased secretion of cortisol later in the
course of the illness (See "HPA axis blunting," above), and because of the rise
in histamine as a result of lack of sufficient methylation capacity to
deactivate it (156).
Slow gastric emptying (157) and gastroesophageal reflux: According to
this Hypothesis, in CFS these result from mitochondrial dysfunction in the
parietal cells of the
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome? (continued)
stomach, due to depletion of reduced glutathione, which results in low
production of stomach acid. (Anecdotally, many CFS patients have reported
absence of eructation after ingestion of sodium bicarbonate solution on an empty
stomach, suggesting low stomach acid status.) A slower rate of gastric emptying
was found to be associated with higher pH, i.e. lower acid status (158).
Gut problems: According to this Hypothesis, several of the above factors
converge to produce problems in the gut in CFS, often referred to as irritable
bowel syndrome (IBS). These factors include glutathione depletion, low cardiac
output, immune suppression, low stomach acid production, neurotransmitter
dysfunction (note that serotonin plays a major role in gut motility), and
increasing variety of infections and inflammation.
The degree of abnormality of a lactulose breath test (indicating small
intestinal bacterial overgrowth) in fibromyalgia patients was found by Pimentel
et al. to be greater than in IBS patients without fibromyalgia (159). In
addition, they found that the abnormality was correlated with somatic pain
(159). (This may be relevant because of the high comorbidity of CFS with
fibromyalgia.)
How does the GD-MCB Hypothesis explain other aspects of chronic fatigue
syndrome? (continued)
Brain-related problems: According to this Hypothesis, several of the
above factors also converge to produce problems in the brain. These include
glutathione (and cysteine) depletion, low cardiac output, failure to defeat
infections and continued immune activation, neurotransmitter dysfunction,
decreased methylation capacity to maintain myelin, and increasing variety of
infections and inflammation.
Relapsing (Crashing) (160): Many CFS patients have chronically low
glutathione levels. According to this Hypothesis, when the level of stressors is
temporarily increased, the levels of reduced glutathione become more severely
depleted, and this produces the so-called crashing phenomenon. After a period of
rest, reduced glutathione levels are increased to the chronically low levels
that existed prior to the increased stressors.
Alcohol intolerance (161): According to this Hypothesis, because of
mitochondrial dysfunction, the skeletal muscles of CFS patients depend more than
normal on glycolysis for ATP production. Increased use of glycolysis requires
increased use of gluconeogenesis by the liver to convert lactate and pyruvate
back to glucose (Cori cycle). In CFS, this is hampered by low cortisol levels.
The metabolism of ethanol by the liver further inhibits gluconeogenesis,
How does the GD-MCB Hypothesis explain other aspects of
chronic fatigue syndrome? (continued)
producing hypoglycemia and lactic acidosis. This accounts for the alcohol
intolerance reported by many CFS patients.
Weight gain: According to this Hypothesis, the weight gain often seen in
CFS results from the inability to metabolize carbohydrates and fats at normal
rates, because of partial
blockades in the Krebs cycle produced by depletion of reduced glutathione.
Excess carbohydrates are cycled back to glucose by gluconeogenesis, and
ultimately are converted to stored fat.
Low serum amino acid levels (19): According to this Hypothesis, these
result from the burning of amino acids as fuel at higher rates than normal.
Amino acids are able to enter the Krebs cycle by anaplerosis, downstream of the
partial blockades, so they can be used as fuel in place of carbohydrates and
fats.
The pathogenesis of CFS becomes increasingly complex as it proceeds, because
of the interactions and feedback loops that develop. For this reason,
determining the cause-effect relationships for all the aspects of the resulting
pathophysiology is a problem that is exceedingly difficult. Nevertheless,
understanding the etiology and early pathogenesis provides a basis for
developing a more effective treatment approach.
CONCLUSIONS
There is abundant and compelling evidence that the glutathione depletion—methylation
cycle block mechanism is an important part of the pathogenesis for at least a
substantial subset of chronic fatigue syndrome patients.
A pathogenesis hypothesis based on this mechanism is capable of explaining
and unifying many of the published observations regarding chronic fatigue
syndrome, and it provides a basis for developing a more effective treatment
approach.
(A Yahoo discussion group is now devoted to these
topics. You can find it at
http://health.groups.yahoo.com/group/CFS_Yasko/)
Treatment suggestions: A
Simplified Approach (Jan 2007) /
Updated Version (July 2007)
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