A HYPOTHESIS FOR THE PATHOGENESIS OF CHRONIC FATIGUE SYNDROME

by

Richard A Van Konynenburg, Ph.D.
(Independent Researcher and Consultant)

richvank@aol.com



8th International IACFS Conference on
Chronic Fatigue Syndrome, Fibromyalgia
and other Related Illnesses

Ft. Lauderdale, Florida, U.S.A.
January 10-14, 2007
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 DepletionMethylation 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?
(See diagram http://www.co-cure.org/scan0003.bmp )

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.

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.

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 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 DepletionMethylation 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?
(continued)

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.

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).

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).

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 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 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.)

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 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
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).


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 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.)

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,
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
depletionmethylation 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.



KEY TO DIAGRAM (See http://www.co-cure.org/scan0003.bmp )


The diagram shows the methylation cycle at the top right, the folate cycle
at the top left, and the transsulfuration pathway at the bottom right.

The enzymes that catalyze the reactions are shown in boxes:

BHMT Betaine homocysteine methyltransferase
CBS Cystathionine beta synthase
CDO Cysteine dioxygenase
CGL Cystathionine gamma lyase
GCL Glutamate cysteine ligase
GS Glutathione synthase
MAT Methionine adenosyltransferase
MS Methionine synthase
MSR Methionine synthase reductase
MTase Methyltransferase (a class of enzymes)
MTHFR Methylene tetrahydrofolate reductase
SHT Serine hydroxymethyltransferase
TS Thymidylate synthase

Most of the metabolites are spelled out. The ones that are abbreviated are
as follows:

DMG Dimethylglycine
SAH S-Adenosylhomocysteine
SAM S-Adenosylmethionine
THF Tetrahydrofolate
TMG Trimethylglycine (betaine)

The cofactor and coenzyme are as follows:

P5P Pyridoxal phosphate, the active form of
Vitamin B6
B12 Methylcobalamin, one of the active forms of
Vitamin B12
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