(AACFS Seventh International Conference Madison, Wisconsin, October 8-10, 2004)
WHAT IS GLUTATHIONE? [Refs. 1--5]
A tripeptide
composed of the amino acids glutamic acid,
cysteine, and glycine. Its molecular weight is 307.33 Da.
Found in all cells in the body, in the bile, in the
epithelial lining fluid of the lungs, and, at much smaller
concentrations, in the blood.
The predominant nonprotein thiol (molecule containing an S-H
or
sulfhydryl group) in cells.
Its active form is the chemically reduced form, called "GSH."
GSH is compartmentalized, with concentrations
ranging from
0.5 to 10 millimolar
in various organs and cell types.
GSH serves as a substrate for enzymes, including
the
glutathione
peroxidases and the glutathione-S-transferases.
When oxidized,
two glutathione molecules join together via a
disulfide bond to form "oxidized glutathione," or "glutathione
disulfide," referred to as "GSSG."
Inside cells, the concentration of GSSG is normally
maintained at less than 1% of total glutathione by the enzyme
glutathione reductase, which is powered by NADPH, produced by the
pentose
phosphate shunt, part of carbohydrate metabolism.
WHAT
ARE SOME OF THE FUNCTIONS OF GLUTATHIONE (GSH)?
[Refs. 1--5]
Maintains
proper oxidation-reduction (redox) potential
inside
cells. Redox affects the oxidation state of sulfur in
enzymes, and thus affects the rates of biochemical reactions in
cells.
Scavenges peroxides and oxidizing free radicals directly and
also
serves as the basis for the antioxidant network.
Performs Phase II detoxication of heavy metals (such as
mercury), organophosphate pesticides, chlorinated hydrocarbon
solvents, estradiol, prostaglandins, leukotrienes, acetaminophen,
and
other foreign and endogenous toxins.
Stores and transports cysteine throughout the body.
Transports amino acids into cells, especially cystine into
kidney
cells.
Regulates the cell cycle,
DNA and protein
synthesis and
proteolysis, and gene
_expression.
Regulates
signal transduction.
Participates in bile production.
Protects thyroid cells from self-generated hydrogen peroxide.
By
means of several of the above functions,
GSH plays very important
roles in (1)
maintaining mitochondrial function and integrity, (2)
regulating cell
proliferation, and (3) supporting the immune
system.
HOW IS GLUTATHIONE (GSH) SYNTHESIZED IN THE BODY? [Refs. 1--5]
GSH is synthesized inside cells by a two-step
process. The
first step involves
the ATP-powered enzyme glutamate cysteine
ligase (formerly
called gamma-glutamylcysteine synthetase). This
step is
normally the rate-limiting reaction, and is controlled by
the
cellular redox state and feedback inhibition, among other
factors. The second step makes use of the ATP-powered enzyme
glutathione synthetase.
The necessary substrates are cysteine (which is often the
rate-limiting substrate when
GSH is depleted),
glutamic acid (or
glutamine) and
glycine. Cysteine and glutamic acid are joined
together in the first
step, and glycine is added in the second step.
The liver is the main producer and exporter of
GSH.
A few
epithelial cell types can import
GSH molecules
intact.
Most cell
types use the gamma glutamyl (or
GSH scavenging)
cycle. This cycle
makes use of the plasma-membrane-bound exoenzymes
gamma-glutamyl
transpeptidase and dipeptidase. This cycle
disassembles
GSH outside the cell and
imports the parts for
reassembly inside.
It also serves as a transport mechanism to bring
other amino acids
into the cell, cystine(di-cysteine)
being favored.
IS
GLUTATHIONE DEPLETED IN CHRONIC FATIGUE SYNDROME?
There is considerable
evidence that it is, at least in a substantial
fraction of
CFS patients. Here are
the results of all the published
studies that bear on
this question:
GSH depletion in CFS was first suggested by Droge
and Holm
[6].
Cheney [7,8]
reported that his
CFS clinical patients
were
almost universally
low in
GSH.
Richards et
al. [9] found that patients could be divided
statistically into
two distinct groups, one having significantly
elevated erythrocyte
GSH relative to a
healthy control group, and
the other having
significantly lower values.
Fulle et al.
[10] found elevated total (reduced plus
oxidized) glutathione in muscle biopsy specimens from PWCs relative
to
healthy controls, but they did not report values for reduced
glutathione alone.
Manuel y Keenoy et al. [11] found that a subgroup of
fatigued patients with low magnesium, whose body stores of Mg did
not
improve with supplementation, had significantly lower
GSH.
Manuel y
Keenoy et al. [12] did not find a significant
difference between
CFS patients and fatigued controls in terms of
whole-blood
GSH, but they did not compare with a healthy
control
group.
Kennedy et al.
[13] found significantly lower red blood cell
GSH in PWCs compared to healthy controls (p=0.05).
Kurup and
Kurup [14] found significantly lower red blood
cell
GSH in myalgic encephalomyelitis patients compared
to healthy
controls (p<0.01).
IN THE GENERAL
POPULATION, WHAT FACTORS OR CONDITIONS ARE KNOWN TO
CAUSE DECREASES IN
INTRACELLULAR GLUTATHIONE CONCENTRATIONS?
These factors and
conditions can be divided into three groups:
The first group is made up of those that (1) lower the rate
of
GSH synthesis or the rate of reduction of GSSG to
GSH, or (2)
raise the rate of
export of
GSH from cells, or (3)
lead to loss of
GSH from the scavenging pathway. This group
includes the
following: genetic
defects [15], elevated adrenaline secretion [16-
20] due to various
types of stress, deficient diet [1] or fasting
[21],
surgical trauma [21,22], burns [23], and morphine [24].
The second group is comprised of toxins that conjugate
GSH
and remove it from
the body [25], such as organophosphate
pesticides,
halogenated solvents, tung oil (used on furniture),
acetaminophen and some types of inhalation anesthesia.
The third group is comprised of conditions that raise the
production rates of reactive oxygen species high enough to produce
oxidative stress, causing cells to export GSSG. These include
strenuous or extended exercise [26], infections (producing leukocyte
activation) [21], toxins that produce oxidizing free radicals during
Phase I
detoxication by cytochrome P450 enzymes [21], ionizing
radiation [27], iron overload [28], and ischemia--reperfusion events
(such
as stroke, cardiac arrest, subarachnoid hemorrhage, and head
trauma)
[29].
STRESS, DISTRESS, AND STRESSORS
For purposes
of this presentation, stressors are defined in
the broad sense as
events, circumstances or conditions that place
demands
on a person and tend to move his or her body out of
allostatic balance. Allostasis is similar to homeostasis, but
allows
for changes in the set-point over time to match life
circumstances [30]. Stressors can be classified as physical,
chemical, biological, or psychological/emotional.
Stress is the state that results from the presentation of
such
demands. Selye [31] defined stress as "the state manifested by
a
specific syndrome which consists of all the nonspecifically-
induced
changes within a biologic system." Although Selye
emphasized the nonspecifically-induced responses, the body also
exhibits specific responses that depend on the type of stress [32].
Stress can be of a beneficial or a destructive nature.
Distress is the destructive type of stress [31].
The perceived stress that people experience depends not only
on the
stressors to which they are subjected, but also on "their
appraisals of the situation and cognitive and emotional responses to
it."
[33]
A person's history of both the occurrence of stressors and
of the
degree of perceived stress can be evaluated by structured
interviews, and this has been done in a number of studies of
CFS
risk factors.
IS THERE EVIDENCE FOR
HIGHER OCCURRENCE OF STRESSORS IN CFS PATIENTS
PRIOR TO ONSET THAN
IN HEALTHY
NORMAL CONTROLS?
YES. The types of
stressors found to have higher occurrence in one
or more
CFS risk factor studies [34-45] include the
following:
Physical:
Aerobic exercise (especially of long duration),
physical trauma
(especially motor vehicle accidents) and surgery
(including anesthesia).
Chemical: Exposure to toxins such as organophosphate
pesticides, solvents and ciguatoxin.
Biological: Infections, immunizations, blood transfusions,
insect
bites, allergic reactions, and eating or sleeping less.
Emotional/Psychological:
Stressful life events, including death of a spouse, close family
member
or close friend; recent marriage; troubled or failing
marriage, separation, or divorce; serious illness in immediate
family;
job loss, starting new job, or increased responsibility at
work;
and residential move.
Difficulties, including ongoing problems with relationships,
persistent work problems or financial problems, mental or physical
violence, overwork, extreme sustained activity, or "busyness."
Dilemmas "A dilemma is a situation in which a person is challenged
to
choose between two equally undesirable alternatives."[45]
Choosing inaction in response to a dilemma leads to further negative
consequences.
Problems in childhood, including significant depression or anxiety,
alcohol
or other drug abuse, and/or physical violence in parents or
other
close family members; physical, sexual or verbal abuse, low
self-esteem and chronic tension or fighting in the family.
IS THERE EVIDENCE FOR
HIGHER PERCEIVED STRESS IN CFS PATIENTS PRIOR
TO ONSET, COMPARED TO
HEALTHY CONTROLS?
YES. Three studies
[34, 37, 38] found that
CFS patients rated their
level of perceived
stress prior to onset higher than did healthy,
normal controls for a
similar period of time.
IN
VIEW OF THE STRONG CORRESPONDENCE BETWEEN THE RESULTS OF THE
CFS
RISK FACTOR STUDIES
AND THE KNOWN GSH DEPLETORS, IT IS NOT
SURPRISING THAT
GLUTATHIONE BECAME DEPLETED IN MANY
CFS PATIENTS.
It appears that the
CFS patients who were studied had undergone a
variety of factors
and conditions that are known to deplete
glutathione.
HOW
DOES THE NEUROENDOCRINE SYSTEM RESPOND TO STRESS?
This system
manifests both specifically- and nonspecifically-
induced responses to
stress [32]. The nonspecifically-induced
responses address the combined load of all the various types of
stress
that are being experienced simultaneously.
The nonspecific responses are mediated by three parts of
this
sytem: (1) the hypothalamus-pituitary-adrenal (HPA) axis, which
produces cortisol and other glucocorticoids, (2) the sympathetic-
adrenomedullary system, which produces epinephrine (adrenaline), and
(3) the
sympathoneural system, which produces norepinephrine
(noradrenaline)
[32].
Rapid-onset
CFS patients report that
they had a normal
response to stress
prior to their onset of
CFS. Therefore, it can
be surmised that if
they experienced a high load of combined long-
term stress lasting a
few months to several years prior to their
onset,
they were subject to high levels of both cortisol and
adrenaline during this extended period of time.
Note that depleted rather than elevated cortisol levels are
frequently observed clinically in
CFS patients (Cleare [46]).
However, the decrease
in cortisol secretion occurs later in the
pathogenesis: "
the
bulk of the data assembled to date is
compatible with the view that the disruption in adrenocortical
function is a late finding, and that elucidating the status of the
central
nervous system components which drive the regulation of the
HPA
axis would be crucial to a more complete understanding of this
final
event." (Demitrack [47])
WHAT ARE THE EFFECTS OF
LONG-TERM ELEVATED LEVELS OF CORTISOL AND
ADRENALINE ON THE
IMMUNE SYSTEM
AND ON GLUTATHIONE
LEVELS?
Elevation of
cortisol is known to suppress the inflammatory
response by several
mechanisms, including decreasing the _expression
of
cytokines and cell adhesion molecules, and decreasing the
production of prostaglandins and leukotrienes [48]. This effect is
beneficially used therapeutically in many cases, but it can also
have a
down side if an infection is present.
Long-term elevation of cortisol is also known to suppress
cell-mediated immunity and to cause a shift to the Th2 type of
immune
response. Several mechanisms are involved, including
suppressing the secretion of IL-1 by macrophages, inhibiting the
differentiation of monocytes to macrophages, inhibiting the
proliferation of T lymphocytes, and increasing the production of
endonucleases, which increases the rate of apoptosis of lymphocytes
[33,48].
Long-term elevation of adrenaline can be expected to deplete
GSH, because adrenaline decreases the rate of
synthesis of
glutathione by the
liver (Estrela et al. [18]), increases its rate
of export from the
liver (Sies and Graf [16]; Haussinger et al.
[17];
Estrela et al. [18]), and decreases the rate of reduction
(recycling) of oxidized glutathione (Toleikis and Godin [19]).
HOW DO VIRAL INFECTIONS
ARISE AT THE ONSET OF CHRONIC FATIGUE
SYNDROME?
I propose that
glutathione depletion is the trigger for reactivation
of
endogenous latent viruses in
CFS (hypothesis).
Here's the support
for this hypothesis:
Most of the
evidence points to reactivation of latent
endogenous viruses at the onset of
CFS, rather than new, primary
infections (Komaroff
and Buchwald [49])
Infections by
members of the Herpes family of viruses, such
as
Epstein-Barr virus and HHV-6 are commonly found in
CFS patients
[49].
GSH depletion is associated with the activation of
several
types of viruses
[50-53], including Herpes simplex type 1 (HSV-1)
[54]. Raising the
GSH concentration inhibits replication of HSV-1
by blocking the
formation of disulfide bonds in glycoprotein B, a
protein that is
necessary for proliferation of the virus [54].
Glycoprotein B is also found in all other Herpes family
viruses
studied, including EBV and CMV [55], and very likely is
present
also in HHV-6 and performs the same vital function there
(hypothesis).
It thus
appears very likely that
GSH depletion is the
trigger for
the reactivation of
the latent forms of all the Herpes family
viruses
(hypothesis). Since glutathione likely becomes depleted
prior
to the onset of
CFS, and since
infections by these viruses are
commonly found in
CFS, it seems likely that glutathione depletion is
responsible for
initiating the viral infections at the onset of
CFS
(hypothesis).
CAN ELEVATED CORTISOL
AND DEPLETED GLUTATHIONE EXPLAIN THE IMMUNE
DYSFUNCTIONS?
YES
The shift to the Th2 immune response, as observed in
CFS
[56], is a known
effect of both elevated cortisol [57] and of
depleted
GSH [58, 59]. I suggest that elevated cortisol
produces
the Th2 shift
initially, and that it is maintained later in the
pathogenesis by
GSH, after the cortisol level drops, due to
blunting
of the HPA axis.
The following
dysfunctions seen in
CFS [60] are known
effects of depleted
GSH: lowered natural killer cell and cytotoxic
T cell cytotoxicity;
and inability of T cells to proliferate, as
seen in decreased
mitogen-induced proliferative response of
lymphocytes and decrease in delayed-type hypersensitivity [61].
In
addition, I hypothesize the following:
The observed chronic immune activation and the observed
continuous activation of the RNase-L pathway in
CFS result from the
failure of
cell-mediated immunity to defeat detected infections,
owing to the above
effects.
The observed low molecular weight RNase-L results from lack
of
inhibition of caspases because of thiol (GSH)
depletion, and they
cleave the RNase-L. (Caspases
are normally inhibited by thiols.)
The observed
elevated numbers of immune complexes result
from
the failure of cell-mediated immunity and the shift to the Th2
response, which produces elevated levels of antibodies.
The observed elevation in antinuclear antibodies results
from
the observed higher rate of apoptosis, which is a known
consequence of
GSH depletion.
HOW DOES PHYSICAL
FATIGUE ARISE AT THE ONSET OF CFS?
(HYPOTHESIS)
When the
immune system detects the viral infection, it
becomes
activated.
In attempting to proliferate, the lymphocytes draw upon the
already
depleted supplies of
GSH and its precursor,
cysteine (or
cystine).
Being in the
blood, the lymphocytes have earlier access to
GSH and cysteine than do the skeletal muscles.
Competition in
CFS between the immune system and the
skeletal muscles for
these substances has already been hypothesized
by Bounous and Molson
[], and I agree with their hypothesis.
The skeletal muscles become more depleted in
GSH.
This produces
a rise in their concentration of
peroxynitrite. (Peroxynitrite
forms from superoxide and nitric
oxide.
Superoxide becomes elevated because the depletion of
GSH
causes a rise in
hydrogen peroxide, and this exerts product
inhibition on the
superoxide dismutase reaction, causing superoxide
levels
to rise.)
As Pall [] has stated, "Peroxynitrite reacts with and
inactivates several of the enzymes in mitochondria so that
mitochondrial and energy metabolism dysfunction is one of the most
important consequences of elevated peroxynitrite."
The resulting partial blockades in the Krebs cycles and the
respiratory chains in the red, slow-twitch skeletal muscle cells
decrease their rate of production of ATP. Since ATP is what powers
muscle
contractions, the lack of it produces physical fatigue. It
becomes
chronic because
GSH remains depleted.
SINCE GLUTATHIONE IS AT
THE BASIS OF THE BODY'S ANTIOXIDANT SYSTEM,
ITS DEPLETION CAN BE
EXPECTED TO PRODUCE OXIDATIVE STRESS.
HAS THIS
BEEN OBSERVED IN
CFS?
YES. Oxidative
stress is now well-established in
CFS.
The following
researchers have presented evidence for oxidative
stress in
CFS:
Ali (1990 and
1993)
Cheney (2000a
& b)
Richards et al. (2000a & b)
Fulle et al. (2000)
Manuel y Keenoy et al. (2001)
Vecchiet et al. (2003)
Kennedy et al. (2003)
Smirnova and Pall (2003)
SINCE GLUTATHIONE
NORMALLY REMOVES MERCURY FROM THE BODY, ITS
DEPLETION CAN BE
EXPECTED TO ALLOW BUILDUP OF MERCURY IN
CFS
PATIENTS. IS THIS
OBSERVED?
YES. While there are
no published controlled studies of mercury
level
testing in
CFS patients, several
clinicians who specialize in
treating
CFS have reported that many of their patients have
high
mercury levels:
Ali (1995)
Godfrey (1998)
Conley (1998)
Poesnecker (1999)
Teitelbaum (2001)
Corsello (2002)
Goldberg (2004)
In
addition, immune testing has shown significantly elevated
hypersensitivity to mercury in many
CFS patients (Stejskal et al.,
1999; Sterzl et al.,
1999; and Marcusson, 1999). This suggests that
the immune system has
responded to elevated mercury levels.
(Note
that there have been epidemiological studies that showed no
evidence that dental amalgams are associated with
CFS as a causal
factor. However,
this does not constitute evidence that amalgams do
not give rise to
elevated mercury levels after
CFS onset in people
who have amalgams and
who may have developed
CFS as a result of
other causes.)
CAN GLUTATHIONE
DEPLETION EXPLAIN AUTOIMMUNE THYROIDITIS IN CHRONIC
FATIGUE SYNDROME?
YES.
It is known that thyroid cells normally produce hydrogen
peroxide to oxidize iodide ions as part of the pathway for producing
thyroid
hormones. Normally, this oxidation occurs outside the cell
membrane, and the interior of the cell is protected from the
hydrogen peroxide by intracellular
GSH (Ekholm and Bjorkman, 1997).
It has been
shown by Duthoit et al., (2001) that if hydrogen
peroxide is allowed
to enter thyroid cells, it will attack and
cleave
thyroglobulin, producing C-terminal fragments that can
diffuse
into other cells and are recognized by autoantibodies from
patients with autoimmune thyroid disease. This suggests that
hydrogen peroxide entry into thyroid cells may be the cause of this
disease.
It has been shown by Wikland et al. (2001), using fine
needle
aspiration cytology, that about 40% of patients suffering
from
chronic fatigue show evidence of chronic autoimmune
thyroiditis, even though
TSH levels were in the
normal range in many
of them.
HYPOTHESIS:
It seems likely that
GSH depletion accounts
for
this high prevalence.
WHY IS
CFS MORE PREVALENT IN WOMEN THAN IN MEN?
It has been
found recently that the monthly menstrual cycle
in women presents an
additional demand on
GSH that does not occur
in
men. 17-beta
estradiol is elevated in women from the late
follicular phase
through the early luteal phase of the cycle. This
hormone
stimulates the activity of the enzyme glutathione peroxidase
(Serviddio
et al., 2002).
Perhaps this occurs to protect against elevated production
of
reactive oxygen species generated during the rapid growth of the
endometrium.
The resulting reactions depress the endometrial
GSH level
during the time the
estradiol level is high (Serviddio et al., 2002).
HYPOTHESIS: I
propose that this additional demand for
GSH in women
exacerbates the
GSH depletion that occurs as a result of other
causes, and that this
makes women more vulnerable to developing
CFS,
accounting for the
higher observed prevalence of
CFS in women than
in men.
WHAT
APPROACHES HAVE BEEN USED TO BUILD GLUTATHIONE?
Diet high in
sulfur-containing amino acids (as in animal-
based protein, such
as milk, eggs and meat) and antioxidants (as in
fresh
fruits and vegetables).
Diet high in
GSH, e.g. fresh fruits
and vegetables and meats
(Jones et al., 1992).
N-acetylcysteine
together with glutamic acid or glutamine
and
glycine (Clark,
www.cfsn.com), or NAC together with dietary
protein (Quig, 1998).
Non-denatured
whey protein (Bounous et al., 1989)
Oral reduced glutathione (Jones et al., 1989)
Intravenous reduced glutathione (Foster et al., 2003)
Intramuscular reduced glutathione (Salvato, 1998)
Transdermal reduced glutathione skin cream
(www.kirkmanlabs.com)
Sublingual reduced glutathione troches (Schaller,
www.personalconsult.com; Hunjan and Evered, 1985)
Reduced glutathione rectal suppositories (one supplier is
Hopewell Pharmacy, New Jersey)
Reduced glutathione aerosol (Buhl et al., 1990)
Reduced glutathione nasal spray (Testa et al., 1995)
HAS GLUTATHIONE
REPLETION BEEN USED CLINICALLY IN CFS, AND IF SO,
WHAT HAVE BEEN THE
RESULTS?
YES.
Patricia Salvato, M.D. has used intramuscular injections of
GSH
combined with ATP
clinically for several years. In 1998 she
reported on a study
of 276
CFS patients, using 100
mg of GSH and 1
mg of ATP weekly.
After 6 months of treatment, 82% experienced
improvement in
fatigue, 71% experienced improvement in memory and
concentration, and 62% experienced improvement in levels of pain.
Paul
Cheney, M.D. reported in 1999 on his clinical use of oral
undenatured whey protein in
CFS patients. The
dosage varied with
different patients,
up to 40 grams per day. He reported that
several of his
patients improved on this treatment, and some who had
had
active infections with herpes family viruses, mycoplasma, or
chlamydia were cleared of them by this treatment.
John S.
Foster, M.D. and his colleagues reported in 2002 on their
use of
GSH in an intravenous fast push (over 2 to 3
minutes).
Dosage ranged up to
2,500 mg, 1 or 2 times weekly, as part of a
detoxification
protocol used on a variety of patients, including
some
with
CFS. They reported that
the treatment has been promising
in addressing
neurodegenerative and neurotoxic disorders.
IS REPLETION OF
GLUTATHIONE LIKELY TO BE THE COMPLETE ANSWER FOR
TREATING
CFS?
NO.
GSH depletion occurs near the beginning of the
complex pathogenesis
of
CFS. There are likely to be many interactions and
vicious
circles as the
pathogenesis develops into the pathophysiology, and
there may also be
damage that is difficult to correct. The
mediators of such damage would likely be infections, toxins and
reactive oxygen species, all of which are able to build up because
of the
depletion of
GSH. It is likely that
a multifaceted treatment
protocol will be
necessary.
When
GSH repletion is begun in patients who have been
GSH-depleted
for extended periods
of time, their immune and detoxication systems
can begin to function
at higher levels of performance. If their
bodies
have accumulated elevated levels of toxins (especially
mercury) and infections, glutathione repletion can cause significant
Herxheimer-type reactions as pathogens are killed and toxins are
mobilized. Care should be taken to proceed slowly and cautiously in
such
cases in order to avoid moving toxins into the central nervous
system
or exacerbating symptoms to a level that is intolerable to
the
patient.
CONCLUSION
Glutathione depletion is an important aspect of the pathogenesis of
chronic
fatigue syndrome for at least a substantial fraction of
patients.
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