Transcript Methylation and Glutathione, Keys to Chronic

Methylation and Glutathione,
Keys to Chronic Fatigue
Syndrome
Rich Van Konynenburg, Ph.D.
Independent Researcher/Consultant
[email protected]
Orthomolecular Health Medicine Society
14th Annual Scientific Meeting
San Francisco
February 29-March 2, 2008
The Bottom Line
•
A comprehensive biochemical hypothesis has been developed to explain the etiology,
pathogenesis, pathophysiology and symptomatology of chronic fatigue syndrome
(CFS).
•
The key biochemical features of this hypothesis are a chronic partial block of the
methylation cycle at methionine synthase and a chronic depletion of glutathione.
•
This hypothesis explains the observed genetic predisposition, observed biochemical
abnormalities, and many seemingly disparate symptoms of CFS as reported in the
peer-reviewed literature and as observed clinically.
•
Lab testing is available to test this hypothesis and to determine whether it applies to a
particular patient. So far it appears to apply to most CFS patients.
•
This hypothesis is also being tested by using orthomolecular treatment including
biochemically active forms of vitamin B12 and folate. It is currently being applied to at
least several hundred patients by at least ten clinicians and is producing significant
benefits in most patients. A preliminary clinical study of this treatment is planned.
Topics to be covered
•
History of the Glutathione Depletion—Methylation Cycle Block (GDMCB) hypothesis
•
Description of glutathione
•
Description of the methylation cycle and associated biochemical
pathways
•
Etiology of CFS, according to this hypothesis
•
Pathogenesis of CFS, according to this hypothesis
•
The role of genetic polymorphisms in CFS
•
Accounting for observed biochemical abnormalities, pathophysiology
and symptoms of CFS with this hypothesis
Topics to be covered (continued)
• Why is CFS more prevalent in women?
• Lab testing to test this hypothesis and to determine whether it
applies to a given case of CFS
• Hypothesis testing using a treatment based on this hypothesis
• Results of hypothesis testing to date
• Some questions that remain to be answered
• Planned clinical study
• References
History of GD-MCB Hypothesis
•
The presence of numerous disparate symptoms in CFS suggested to the
present author that there must be a fundamental biochemical anomaly
affecting many cell types.
•
Paul Cheney, M.D. reported “almost universal” glutathione depletion in CFS
in 1999 [1,2] Derek Enlander, M.D. [3] and Patricia Salvato, M.D. [4] had
been treating CFS patients with glutathione for some years.
•
The present author reported in October, 2004, that many of the features of
CFS can be accounted for directly by glutathione depletion, but that direct
attempts to raise glutathione were transitory. Vicious circles were
suspected [5].
•
S. Jill James, Ph.D., et al. reported that in autism there is glutathione
depletion combined with methylation cycle block. Lifting the methylation
cycle block using methylcobalamin, folinic acid and betaine also restored
normal levels of glutathione, suggesting that these two phenomena are
linked (Dec. 2004) [6].
History of GD-MCB Hypothesis
(continued)
•
The present author noted similarities in biochemistry and some symptoms between
autism and CFS, and suspected that the same mechanism was involved, so that
similar treatments should be effective [7]. A few people with CFS began trying Defeat
Autism Now (DAN!) and Yasko treatments.
•
The present author presented the GD-MCB hypothesis for CFS at the IACFS
conference in January, 2007 [8]
•
In late January, 2007, the present author suggested hypothesis testing using an
orthomolecular simplified treatment approach for CFS (involving seven supplements)
extracted from the complete treatment program of Amy Yasko, Ph.D., N.D., used
primarily in autism [9].
•
Starting on Feb. 19, 2007, some CFS patients began trying the simplified treatment
approach. Number of supplements was decreased to five. Cost became less than
$3.00 per day. Initial results were quite striking. Use spread via on-line support
groups, and soon a few clinicians started using it in their practices, some in response
to reports from their patients. Currently there are at least several hundred CFS
patients being treated for methylation cycle block worldwide, and most are reporting
continuing improvement. Structured clinical trials have not yet been performed.
Glutathione—What is it and what
does it do?
(10-14)
•
•
•
•
•
•
•
•
•
•
•
•
A tripeptide, composed of glutamate, cysteine and glycine
Found in all cells, blood, bile and epithelial lining fluid of the lung
Synthesized by cells, particularly in the liver
The most abundant thiol-containing substance in cells
Has reduced and oxidized forms, GSH and GSSG
Ratio of GSH to GSSG controls the redox potential in cells
Serves as basis for the antioxidant system, quenching reactive
oxygen species
Conjugates several classes of toxins for removal from the body in
Phase II detox, and quenches free radicals generated in Phase I
detox in general
Supports immune system, especially cell-mediated immunity
Plays important role in synthesis of proteins that contain cysteine
Participates in bile production
Has many other roles
Methylation cycle and associated
biochemical pathways
(15-20)
Folate cycle
dietary
protein
Methylation cycle
methionine
methionine
synthase
homocysteine
Transsulfuration
pathway
cysteine
Sulfoxidation and synthesis
of taurine and sulfate
glutathione
(GSH)
What does the methylation cycle
do?
(21)
• Supplies methyl (CH3) groups for a large
number of biochemical reactions in the body.
• Controls the overall sulfur metabolism, balancing
the needs for methyl groups, for GSH to control
oxidative stress, and for other sulfur metabolites,
including cysteine, taurine and sulfate.
• Coordinates the production of new DNA with the
supply of methyl groups, which are used to
methylate DNA, among many other roles.
(basic) Methylation cycle
methionine
MAT
S-adenosylMethionine
(SAMe)
MTR, MTRR
MTs
S-adenosylHomocysteine
(SAH)
homocysteine
ACHY
(15-20)
(basic) Methylation cycle with
BHMT pathway added
(15-20)
[Note that BHMT is found only in liver and kidney cells(22).]
methionine
MAT
DMG
MTR, MTRR
MTs
BHMT
TMG
(betaine)
homocysteine
S-adenosylmethionine
S-adenosylhomocysteine
AHCY
(complete) Methylation cycle
dietary
protein
methionine
NADPH
MTR, MTRR
MAT
DMG
MTs
BHMT
TMG
(betaine)
B12
homocysteine
S-adenosylmethionine
S-adenosylhomocysteine
AHCY
adenosine
(15-20)
ATP
PPi + Pi
methyl
acceptor
methylated
product
H2O
(basic) Folate cycle
THF
TS
SHMT
MTR MTRR
MeB12
5,10methylene
THF
5-Methyl
THF
MTHFR
(15-20)
(more complete) Folate cycle
thymidine
synthesis
(for DNA)
dUMP
THF
TS
SHMT
P5P
(B6)
5,10methylene
THF
MTR MTRR
glycine
MeB12
5-Methyl
THF
MTHFR
purine
synthesis
(for DNA/RNA)
serine
(15-20)
(combined) Methylation and Folate
cycles
(15-20)
[Note that the methylation cycle and the folate cycle are present in all cells of the body (22).]
thymidine
synthesis
(for DNA)
dUMP
dietary
protein
ATP
methionine
MAT
THF
TS
NADPH
SHMT
P5P
(B6)
5,10methylene
THF
serine
MTR MTRR
glycine
5-Methyl
THF
DMG
MTs
BHMT
TMG
(betaine)
B12
homocysteine
S-adenosylmethionine
S-adenosylhomocysteine
AHCY
MTHFR
purine
synthesis
(for DNA/RNA)
adenosine
PPi + Pi
methyl
acceptor
methylated
product
H2O
(combined) Methylation and Folate
cycles (showing link to transsulfuration
pathway via CBS)
(15-20)
thymidine
synthesis
(for DNA)
dUMP
dietary
protein
ATP
methionine
MAT
THF
TS
NADPH
SHMT
P5P
(B6)
5,10methylene
THF
serine
MTR MTRR
glycine
5-Methyl
THF
DMG
MTs
BHMT
TMG
(betaine)
B12
S-adenosylmethionine
homocysteine
S-adenosylhomocysteine
AHCY
MTHFR
purine
synthesis
(for DNA/RNA)
CBS
P5P
(B6)
adenosine
PPi + Pi
methyl
acceptor
methylated
product
H2O
Transsulfuration pathway
(15-20)
[Note that a complete transsulfuration pathway is found only in cells of the liver, kidneys, pancreas,
intestine, lens of the eye, and (at much lower capacity) the brain (22-24).]
homocysteine
serine
CBS
H2O
NH3
P5P
(B6)
P5P
(B6)
protein
synthesis
alphaketobutyrate
cystathionine
dietary
protein
CTH
glycine
glutamate
cysteine
GCL
CDO
ATP
gammaglutamylcysteine
GS
ATP
glutathione
(GSH)
Sulfoxidation and synthesis of
sulfate and taurine
(15-20)
cysteine
alphaketoglutarate
O2
CDO
cysteinesulfinic
acid
GOT2
beta
sulfinylpyruvate
spontaneous
decomposition
pyruvate
CSAD
CO2
glutamate
hypotaurine
O2, H2O
bisulfite
Mo
SUOX
H+, H2O2
sulfate
peroxynitrite?
taurine
½ O2
Etiology of CFS, according to this
hypothesis
Genetic predisposition (25)
and
1. Some combination of a variety of physical, chemical,
biological and or psychological/emotional stressors, the
particular combination differing from one case to
another, which initially raises cortisol and epinephrine
and depletes intracellular reduced glutathione (GSH)
(1,2,26-30)
or
2. Stressors combined with genetic polymorphisms in
enzymes that use glutathione (GSH) (31)
Most common pathogenesis of CFS,
according to this hypothesis
1. Stressors lower glutathione (GSH) (1,2,26-30), which produces oxidative stress (27, 28,30, 33-44),
allows toxins to accumulate (45-48), and removes protection from B12 (49).
2. Oxidative stress partially blocks methionine synthase (MTR) (50) and shifts cysteine toward cystine.
3. Accumulated toxins (probably especially mercury) react with much of the B12 (49, 51,52).
4. Partial block of methionine synthase (MTR) becomes chronic.
5. Cystathionine-gamma-lyase (CTH) converts cystine to hydrogen sulfide, which is then converted to
thiosulfate (53).
6. Sulfur metabolites drain down to form thiosulfate, which is excreted, lowering methionine.
7. Intracellular cysteine levels become too low to restore glutathione levels to normal.
8. Resulting vicious circle becomes chronic.
Cystathionine gamma lyase (CTH) pathway (53, 54)
diverts cysteine to thiosulfate under oxidative
stress conditions (hypothesis)
oxidative
stress
cysteine
pyruvate
cystine
CTH
thiocysteine
cysteine
non-enzymatic
decomposition
hydrogen
sulfide
bisulfite
SUOX
NH4+
?
oxygen
thiosulfate
reductase?
thiosulfate
H2O
GSH
GSSG
hydrogen
sulfide
Mo
sulfate
A less common pathogenesis,
according to this hypothesis
1.There are genetic polymorphisms in glutathione peroxidases (GPx)
and/or glutathione transferases (GST’s), so that glutathione is not
effectively used (31).
2. Stressors lead to same effects as above, even though glutathione
levels do not drop, and may even be elevated (27).
3. Oxidative stress leads to partial block of methionine synthase (MTR)
(50) and toxins build up (45-48), reacting with B12 (49, 51, 52).
4. Partial block becomes chronic.
Why do these pathogenetic processes take place
in the people who develop CFS, but not in other
people?
• A major factor is likely to be differences in the combinations of
inherited genetic polymorphisms.
• There has not yet been a complete genome study of the
polymorphisms that are more frequent in CFS than in the general
population.
• There is evidence from family and twin studies as well as limited
polymorphism studies that there is a genetic component in the
development of CFS (25).
Genetic polymorphisms (SNPs) associated with
CFS
•
So far, SNPs in genes for the following proteins have been found to be present at higher frequency in CFS
in general or in a subset, either alone or in combination:
Immune system:
–
–
Tumor necrosis factor (TNF) (55)
Interferon gamma (IFN-gamma) (55)
Neurotransmitter systems:
–
–
–
–
–
–
Tryptophan hydroxylase 2 (TPH2) (56,57)
Serotonin transporter (5-HTT) gene promoter (58)
Serotonin receptor subtype HTR2A (25)
Monoamine oxidase A (MAO A) (56)
Monoamine oxidase B (MAO B) (56)
Catechol-O-methyltransferase (COMT) (57)
HPA Axis:
–
–
–
–
Angiotensin converting enzyme (ACE) (59)
Proopiomelanocortin (POMC) (56)
Corticosteroid binding globulin (CBG) (60)
Glucocorticoid receptor--nuclear receptor subfamily3, group C, member 1 (NR3C1) (56, 57, 61)
All of these proteins play roles in the pathogenesis described by this hypothesis.
Accounting for observed biochemical
abnormalities, pathophysiology and
symptoms with this hypothesis
•
“Gedanken experiment” approach: examine the normal functions of
glutathione and methylation, and consider what might be expected to occur
if these functions were not carried out.
•
It is found that this “gedanken experiment” approach reproduces many
observed features of CFS in detail.
•
Features that were not discovered and explained by this approach can be
traced back to these same causes by starting with the features and
considering what might cause them, i.e. reasoning in the opposite direction.
•
The result of this bidirectional thought process is that essentially all the
observed features of CFS can be specifically accounted for by this
hypothesis.
What are some things that might be expected if
glutathione were depleted, and are they observed
in CFS?
•
•
•
•
•
•
•
•
Oxidative stress—observed (27,28,30,33-44).
Mitochondrial dysfunction and low ATP output, leading, for examples, to
physical fatigue in skeletal muscles—observed; and diastolic dysfunction in
the heart, leading to low cardiac output—observed (62)
Buildup of toxins, including heavy metals—observed (5, 45, 46).
Immune response shift to Th2—observed (63).
Inability of T cells to proliferate in response to mitogens—observed (64).
Reactivation of herpes family viral infections—observed (65).
Thyroid problems—observed (66).
Low secretion and dysregulation of certain cysteine-containing secretory
proteins, including ACTH, antidiuretic hormone, and perforin (67).
Low ACTH leads to blunting of the HPA axis—observed (68), low
antidiuretic hormone leads to high daily urine volumes and constant
thirst—observed (69), and low perforin leads to low cytotoxic activity of
the natural killer cells and the CD8 (“killer”) T cells—observed (70).
What are some things that might be expected if the
methylation capacity were diminished, and are
they observed in CFS?
• Overexpression of many genes because of lack of gene silencing by
methylation—observed (71).
• Lowered synthesis of choline and creatine—abnormal ratio of
choline to creatine observed in brain (72-75).
• Lowered synthesis of carnitine—deficit observed (76).
• Lowered synthesis of coenzyme Q-10—supplementation observed
to be beneficial (77).
• Lowered synthesis of myelin basic protein—slow brain processing
speed observed (78).
How does this hypothesis account for the higher
prevalence of CFS in women than in men?
• During their potentially reproductive years, estrogens are produced
in larger amounts in women, and must be metabolized.
• Some people (both men and women) inherit polymorphisms in the
genes that code for some of the detox enzymes involved in the
metabolism of the estrogens (CYP1B1, COMT and GST enzymes).
• In women, these polymorphisms can lead to redox cycling when
metabolizing estrogens. This adds an additional bias toward
depletion of glutathione and development of oxidative stress.
• Oxidative stress initiates the pathogenesis of CFS.
• (For more details, see 2007 IACFS poster paper: http://phoenixcfs.org/GenderCFSKonynenburg.htm )
Lab testing
• The methylation panel (offered by Vitamin Diagnostics,
Inc., and the European Laboratory of Nutrients) is the
most definitive for detecting methylation cycle block and
glutathione depletion.
• Urine testing for methylmalonic acid and
formiminoglutamic acid (“figlu”) are also very helpful.
When these are elevated, they indicate low
adenosylcobalamin and low tetrahydrofolate,
respectively. When both methylamalonic acid and figlu
are elevated, it is very likely that methionine synthase is
partially blocked.
Methylation panel (Vitamin Diagnostics,Inc. and
European Laboratory of Nutrients)
Metabolites measured:
• S-adenosylmethionine (red blood cells)
• S-adenosylhomocysteine (red blood cells)
• Adenosine
• 5-methyl tetrahydrofolate (serum)
• 10-formyl tetrahydrofolate (serum)
• 5-formyl tetrahydrofolate (folinic acid) (serum)
• Tetrahydrofolate (serum)
• Folic acid (serum)
• Folinic acid (whole blood)
• Folic acid (red blood cells)
• Glutathione (GSH) (serum)
• Oxidized glutathione (GSSG) (serum)
So far, the present author has seen seven results of this panel run on CFS patients.
Six have shown a methylation cycle partial block and depletion of reduced glutathione
relative to oxidized glutathione. The seventh had a methylation cycle block but
normal glutathione levels. Data from more patients are needed.
Testing the GD-MCB hypothesis by
using treatment based on it
• The main goal of such treatment would be to raise the activity of
methionine synthase.
• This appears to be best done by the simultaneous application of
bioactive forms of vitamin B12 and bioactive forms of folate, since
both are required by methionine synthase (MTR), and often both are
deficient.
• Some support for the BHMT pathway would likely also be helpful,
since this promotes synthesis of SAMe, which supports methionine
synthase reductase (MTRR).
• General nutritional support would likely be helpful as well, since
many CFS patients have nutritional deficiencies.
“Simplified Treatment Approach”
•
Derived from part of “step 2” of the full methylation cycle block treatment program
developed by Amy Yasko, Ph.D., N.D. and used primarily in autism (9).
•
Consists of five nutritional supplements, taken daily:
1. Hydroxocobalamin (2,000 micrograms, sublingual)
2. 5-Methyl tetrahydrofolate (200mcg)
3. Combination of [folic acid, 5-methyl tetrahydrofolate, and folinic acid] (200 mcg),
cyanocobalamin (125 mcg), calcium (22.5 mg), phosphorus (17.25 mg), and intrinsic
factor (5 mg)
4. A multivitamin, multimineral supplement including antioxidants, trimethylglycine,
nucleotides, supplements to support the sulfur metabolism, a high ratio of magnesium
to calcium, and no iron or copper (up to two tablets)
5. Phosphatidyl serine complex (one softgel)
Note: Even though this treatment consists only of nutritional supplements, patients
who are on it need to be under the care of a physician, in order that any individual
health issues that may arise may be properly dealt with.
Composition of multi-vitamin, multi-mineral supplement
used in “simplified treatment approach”
•
Serving Size: 6 Tablets (note that up to 2 tablets per day are used in the treatment)
•
Amount per serving: Vitamin A (as palmitate)5000 IU,Vitamin C (ascorbic acid)500
mg,Vitamin D (as cholecaliciferol)400 IU,Vitamin E (as d-alpha tocopheryl
succinate)400 IU,Vitamin K (as phytonadione)40 mcg,Vitamin B-1 (as
benfotiamine)25 mg,Vitamin B-2 (as riboflavin)12.5 mg,Niacin (as niacinamide)37.5
mg,Vitamin B-6 (as pyridoxal-5-phosphate)12.5 mg,Folic Acid100 mcg,Vitamin B-12
(cyanocobalamin B12)250 mcg,Biotin150 mcg,Pantothenic Acid (as d-calcium
pantothenate)50 mg,Calcium (as calcium d-glucarate)25 mg,Magnesium (as citrate,
oxide)100 mg,Zinc (as monomethionine)5 mg,Selenium (as L-selenomethionine)100
mcg,Manganese (as arginate)1 mg,Chromium (as polynicotinate)100
mcg,Molybdenum (as amino acid chelate)75 mcg,Potassium (as citrate)5 mg,Broccoli
florets powder160 mg,Citrus bioflavonoids50 mg,Choline (as bitartrate)25
mg,Inositol25 mg,PABA (para-amino benzoic acid)5 mg,Garlic (Allium sativum) bulb
powder200 mg,L-methionine150 mg,Milk thistle (Silybum marianum) seed extract100
mg,N-acetyl-cysteine75 mg,Pine (Pinus maritimus) bark extract25 mg,Taurine250
mg,Turmeric (Curcuma longa) root extract50 mg,Intrinsic Factor5
mg,Trimethylglycine (TMG)50 mg, Free Form Nucleotide Complex100 mg,Boron1
mg,L-Carnitine (Tartrate)100 mg.
•
(Ref.: http://www.holisticheal.com)
Results of treatment
• Informal reports from clinicians
• Informal reports from patients
Beneficial changes
Detox and die-off symptoms
Serious adverse effects reported by a
few patients.
Informal reports from clinicians (conveyed
with their permission)
• David Bell, M.D. (Lyndonville, NY): “I have a good treatment
response in roughly 50% of my long-term patients who have not
responded particularly well to standard symptom-based therapies. I
am very encouraged…”
• Karen Vrchota, M.D. (Winona, MN): “78 out of 109 patients [72%]
have marked improvement.” Patients are “slowly improving week to
week and month to month. Those started in July 2007 have not
peaked yet; that is, they are still improving.”
• Neil Nathan, M.D. (Springfield, MO): “I’ve got about 75 patients on
the protocol now, and have results from about 60. Roughly, 70%
report noticeable improvement, and 15 to 20% report marked
improvement. 30 to 40 % report reactions in one form or another.
Most of these are very mild.” “It's clear that it does work. We now
have to define how to use it optimally.”
Informal reports from clinicians (conveyed
with their permission) (continued)
• Derek Enlander, M.D. (NYC): Using his own protocol, which
includes methylation cycle treatment (but does not include 5-methyl
THF), Dr. E. reports that he has 112 patients under treatment, and
that 65 to 70% of them show improvement.
• Sarah Myhill, MB BS (Wales): Dr. M. has 10-12 CFS patients on her
methylation supplement package, but does not yet have feedback
from all of them. However, she reports that “There is no doubt that
for some this is a very worthwhile intervention.”
• Jacob Teitelbaum, M.D. (Hawaii): “Some doctors in the
Fibromyalgia and Fatigue Centers of America have started using the
protocol. I am excited about its potential and am awaiting feedback.”
Beneficial changes reported by
various patients
•
•
•
•
•
•
•
•
•
•
•
Improvement in sleep (though a few have reported increased difficulty in
sleeping initially).
Ending of the need for and intolerance of continued thyroid hormone
supplementation.
Termination of excessive urination and night-time urination.
Restoration of normal body temperature from lower values.
Restoration of normal blood pressure from lower values.
Initiation of attack by immune system on longstanding infections.
Increased energy and ability to carry on higher levels of activity without
post-exertional fatigue or malaise. Termination of “crashing.”
Lifting of brain fog, increase in cognitive ability, return of memory.
Relief from hypoglycemia symptoms.
Improvement in alcohol tolerance.
Decrease in pain (though some have experienced increases in pain
temporarily, as well as increased headaches, presumably as a result of
detoxing).
Beneficial changes reported by
various patients (continued)
•
•
•
•
•
•
•
•
•
•
•
•
Notice of and remarking by friends and therapists on improvements in the
patient’s condition.
Necessity to adjust relationship with spouse, because not as much
caregiving is needed. Need to work out more balanced responsibilities in
relationship in view of improved health and improved desire and ability to be
assertive.
Return of ability to read and retain what has been read.
Return of ability to take showers standing up.
Return of ability to sit up for long times.
Return of ability to drive for long distances.
Improved tolerance for heat.
Feeling unusually calm.
Feeling "more normal and part of the world."
Ability to stop steroid hormone support without experiencing problems from
doing it.
Lowered sensation of being under stress.
Loss of excess weight.
Detox and die-off related symptoms
reported by various patients
•
•
•
•
•
•
•
•
•
•
•
•
•
Headaches, “heavy head,” “heavy-feeling headaches.”
Alternated periods of mental “fuzziness” and greater mental clarity.
Feeling “muggy-headed” or “blah” or sick in the morning.
Transient malaise, flu-like symptoms.
Transiently increased fatigue, waxing and waning fatigue, feeling
more tired and sluggish, weakness.
Dizziness.
Irritability.
Sensation of “brain firing: bing, bong, bing, bong,” “brain moving
very fast.”
Depression, feeling overwhelmed, strong emotions.
Greater need for “healing naps.”
Swollen or painful lymph nodes.
Mild fevers.
Runny nose, low grade “sniffles,” sneezing, coughing.
Detox and die-off related symptoms reported
by various patients (continued)
•
•
•
•
•
•
•
•
•
•
•
•
•
Sore throat.
Rashes.
Itching.
Increased perspiration, unusual smelling perspiration.
“Metallic” taste in mouth.
Transient nausea, “sick to stomach.”
Abdominal cramping/pain.
Increased bowel movements.
Diarrhea, loose stools, urgency.
Unusual color of stools, e.g. green.
Temporarily increased urination.
Transiently increased thirst.
Clear urine.
Serious adverse effects reported by
a few patients
•
•
•
•
•
Exacerbation of comorbid autoimmune disease.
Exacerbation of comorbid autonomous multinodular goiter.
Cessation of peristalsis for two weeks.
Persisting low fever of unknown origin.
Flare-up of Lyme disease that had been controlled with antibiotics.
Conclusion from this experience: Even though this treatment
consists only of food supplements, structured clinical trials are
needed to determine the efficacy of this treatment quantitatively and
to learn how it may be safely applied.
Some questions that remain to be
answered
1. For which PWCs would this be an appropriate treatment approach?
2. For what fraction of the entire PWC population will this treatment
approach be beneficial?
3. How can PWCs who are likely to experience adverse effects from
this treatment approach be identified beforehand, so that these
effects can be avoided?
4. Are there PWCs who are too debilitated to be able to tolerate the
detoxing and die-off processes that result from this treatment
approach, and if so, would the full Yasko treatment approach be
suitable for them?
5. Will the simplified treatment approach produce continued
improvement over time for those who are finding it beneficial, and
will they be cured?
6. Will the simplified treatment approach be effective in cases of "pure
fibromyalgia" as it appears to be in many cases of CFS?
7. How can this treatment approach be further improved?
Planned clinical study
•
•
•
•
•
•
•
•
Objective: Determine effectiveness of a treatment to lift the methylation
cycle block
100 patients, satisfying diagnostic criteria for both CFS and fibromyalgia, in
one practice (Neil Nathan, M.D., Springfield, MO)
Informed consent
Lab testing (2X): Methylation panel, characterization of certain
polymorphisms, thyroid panel including autoantibodies
Questionnaires to collect pertinent data and evaluate symptoms (3X)
Treatment—”simplified treatment approach” (five supplements daily)
Patient logs
Treatment duration—six months
This study will not be randomized, doubly blinded, or placebo controlled, but
hopefully it will demonstrate that the treatment is worthy of a more
controlled study.
The Bottom Line
•
A comprehensive biochemical hypothesis has been developed to explain
the etiology, pathogenesis, pathophysiology and symptomatology of chronic
fatigue syndrome (CFS).
•
The key biochemical features of this hypothesis are a chronic partial block
of the methylation cycle at methionine synthase and a chronic depletion of
glutathione.
•
This hypothesis explains the observed genetic predisposition, observed
biochemical abnormalities, and many seemingly disparate symptoms of
CFS as reported in the peer-reviewed literature and as observed clinically.
•
Lab testing is available to test this hypothesis and to determine whether it
applies to a particular patient. So far it appears to apply to most CFS
patients.
•
This hypothesis is also being tested by using orthomolecular treatment
including biochemically active forms of vitamin B12 and folate. It is currently
being applied to at least several hundred patients by at least ten clinicians
and is producing significant benefits in most patients. A preliminary clinical
study of this treatment is planned.
Additional reading
•
Van Konynenburg, R.A., “Is Glutathione Depletion an Important Part of the Pathogenesis of
Chronic Fatigue Syndrome?” poster paper, AACFS 7th Intl. Conf., Madison, WI, October 8-10,
2004
http://phoenix-cfs.org/GluAACFS04.htm
•
Van Konynenburg, R.A., “Glutathione Depletion—Methylation Cycle Block, A Hypothesis for the
Pathogenesis of Chronic Fatigue Syndrome,” poster paper, 8th Intl. IACFS Conf. on CFS,
Fibromyalgia, and Other Related Illnesses, Fort Lauderdale, FL, January 10-14, 2007
http://phoenix-cfs.org/GSHMethylationVanKonynenburg.htm
•
Van Konynenburg, R.A., “Why is the Prevalence of Chronic Fatigue Syndrome Higher in Women
than in Men?” poster paper, 8th Intl. IACFS Conf. on CFS, Fibromyalgia, and Other Related
Illnesses, Fort Lauderdale, FL, January 10-14, 2007
http://www.phoenix-cfs.org/ResGenderCFSKonynenburg.htm
•
Van Konynenburg, R.A., “Simplified Treatment Approach Based on the Glutathione DepletionMethylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS),” article,
July 18, 2007
http://phoenix-cfs.org/GSHMethylDeplTheoryJuly07.htm
and
http://phoenix-cfs.org/GSHMethylTrtPlanJuly07.htm
References
1. Cheney, P.R., Evidence of glutathione deficiency in chronic fatigue syndrome, American Biologics 11 th
International Symposium (1999), Vienna, Austria, Tape no. 07-199, available from Professional Audio
Recording, P.O. Box 7455, LaVerne, CA 91750 (phone 1-800-227-4473).
2. Cheney, P.R., Chronic fatigue syndrome, lecture presented to the CFIDS Support Group of Dallas-Fort
Worth, Euless, TX, on May 15, 1999. Video tape available from Carol Sieverling, 513 Janann St., Euless, TX
76039.
3. Enlander, D., personal communication, 2007.
4. Salvato, P., CFIDS patients improve with glutathione injections, CFIDS Chronicle (Jan/Feb 1998).
5. Van Konynenburg, R.A., “Is Glutathione Depletion an Important Part of the Pathogenesis of Chronic
Fatigue Syndrome?” poster paper, AACFS 7th Intl. Conf., Madison, WI, October 8-10, 200
http://phoenix-cfs.org/GluAACFS04.htm
6. James, S.J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D.W., and Neubrander, J.A., Metabolic
biomarkers of increased oxidative stress and impaired methylation capacity in children with autism,
Clin. Nutrit. 2004; 80:1611-1617.
7. Van Konynenburg, R.A., Chronic fatigue syndrome and autism, Townsend Letter for Doctors and Patients,
October 2006, paper available at
http://www.findarticles.com/p/articles/mi_mOISW/is_279/ai_n16865315/print
8. Van Konynenburg, R.A., “Glutathione Depletion—Methylation Cycle Block, A Hypothesis for the
Pathogenesis of Chronic Fatigue Syndrome,” poster paper, 8th Intl. IACFS Conf. on CFS, Fibromyalgia,
and Other Related Illnesses, Fort Lauderdale, FL, January 10-14, 2007
http://phoenix-cfs.org/GSHMethylationVanKonynenburg.htm
References (continued)
9. Yasko, A. and Gordon, G., The Puzzle of Autism: Putting it All Together, Matrix, Payson, AZ (2006).
10. Wu, G., Fang, Y.-Z., Yang, S., Lupton, J.R., and Turner, N.D., Glutathione metabolism and its implications
for health, J. Nutr. (2004) 134:489-492.
11. Dickinson, D.A., Moellering, D.R., Iles, K.E., Patel, R.P., Levonen, A.-L., Wigley, A., Darley-Usmar, V.M., and
Forman, H.J., Cytoprotection against oxidative stress and the regulation of glutathione synthesis, Biol.
Chem. (2003) 384:527-537.
12. Lu, S.C., Regulation of hepatic glutathione synthesis: current concepts and controversies, FASEB J.
(1999) 13:1169-1183.
13. Kidd, P.M., Glutathione: systemic protectant against oxidative and free radical damage, Alt. Med. Rev.
(1997) 1:155-176.
14. Lomaestro, B.M., and Malone, M., Glutathione in health and disease: pharmacotherapeutic issues, Ann.
Pharmacother. (1995) 29:1263-1273.
15. Devlin, T. M., editor, Textbook of Biochemistry With Clinical Correlations, Sixth Edition, Wiley-Liss,
Hoboken, NJ (2006).
16. Finkelstein, J.D., Inborn errors of sulfur-containing amino acid metabolism, J. Nutr. 136: 1750S-1754S
(2006).
17. Stipanuk, M.H., Londono, M., Lee, J-I., Hu, M., and Yu, A.F., Enzymes and metabolites of cysteine
metabolism in nonhepatic tissues of rats show little response to changes in dietary protein or sulfur
amino acid levels, J. Nutr. 132: 3369-3378 (2002).
References (continued)
18. Pangborn, J., and Baker, S.M., Autism: effective biomedical treatments, Autism Research Institute, San
Diego, CA (2005).
19. Reed, M.C., Nijhout, H.F., Neuhouser, M.L., Gregory, J.F. III, Shane, B., James, S.J., Boynton, A., and
Ulrich, C.M., A mathematical model gives insights into nutritional and genetic aspects of folate-mediated
one-carbon metabolism, J. Nutr. 136: 2653-2661 (2006).
20. Fontana, M., Amendola, D., Orsini, E., Boffi, A. and Pecci, L., Oxidation of hypotaurine and cysteine
sulphinic acid by peroxynitrite, Bichem. J. 389: 233-240 (2005).
21. Deth, R., Muratore, C., Benzecry, J., Power-Charnitsky, V.A., and Waly, M., How environmental and genetic
factors combine to cause autism: a redox/methylation hypothesis, Neurotoxicology 29 (1): 190-201 (2008).
22. Finkelstein, J.D., Methionine metabolism in liver diseases, Am J Clin Nutr 77: 1094-5 (2003).
23. Persa, C., Pierce,A., Ma, Z., Kabil, O., and Lou, M.F., The presence of a transsulfuration pathway in the
lens: a new oxidative stress defense system, Experimental Eye Research 79: 875-886 (2004).
24. Vitvitsky, V., Thomas, M., Ghorpade, A., Gendelman, H.E., and Banerjee, R., A functional transsulfuration
pathway in the brain links to glutathione homeostasis, J Biol Chem 281(47): 35785-35793 (2006).
25. Smith, A.K., Dimulescu, I., Falkenberg, V.R., Narasimhan, S., Heim, C., Vernon, S.D., and Rajeevan, M.S.,
Genetic evaluation of the serotonergic system in chronic fatigue syndrome, Psychoneuroendocrinology
33(2): 188-197 (2008).
26. Droge, W. and Holm, E., Role of cysteine and glutathione in HIV infection and other diseases associated
with muscle wasting and immunological dysfunction, FASEB J (1997),11:1077-1089.
References (continued)
27. Richards, R.S., Roberts, T.K., Dunstan, R.H., McGregor, N.R., and Butt, H.L., Free radicals in chronic
fatigue syndrome: cause or effect?, Redox Report (2000) 5 (2/3):146-147.
28. Manuel y Keenoy, B., Moorkens, G., Vertommen, J., Noe, M., Neve, J., and De Leeuw, I., Magnesium status
and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of
supplementation with magnesium, J Amer Coll Nutrition (2000), 19(3): 374-382.
29. Kurup, R.K., and Kurup, P.A., Hypothalamic digoxin, cerebral chemical dominance and myalgic
encephalomyelitis, Intern J Neurosci (2003), 113:683-701.
30. Kennedy, G., Spence, V.A., McLaren, M., Hill, A., Underwood, C., and Belch, J.J., Oxidative stress levels are
raised in chronic fatigue syndrome and are associated with clinical symptoms, Free Radic Biol Med (2005),
39(5): 584-589.
31. Hashimoto, T., Hashimoto, K., Miyatake, R., Matsuzawa, D., Sekine, Y., Inada, T., Ozaki, N., Iwata, N.,
Harano, M., Komiyama, T., Yamada, M., Sora, I., Ujike, H., and Iyo, M., Association study between
polymorphisms in glutathione-related genes a methamphetamine use disorder in a Japanese population
Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 9 [Epub ahead of print].
32. Babior,B.M., and Bunn, H.F., Chapter 92: Megaloblastic anemias, pp. 601-607 in Harrison’s Principles of
Internal Medicine, 16th edition, D.L. Kasper et al., eds., McGraw-Hill, New York (2005).
33. Ali, M., Ascorbic acid reverses abnormal erythrocyte morphology in chronic fatigue syndrome, abstract,
Am. J. Clin. Pathol. (1990); 94:515.
34. Ali, M., Hypothesis: chronic fatigue is a state of accelerated oxidative molecular injury, J. Advancement in
Med. (1993); 6 (2): 83-96.
References (continued)
35. Richards, R.S., Roberts, T.K., McGregor, N.R., Dunstan, R.H., and Butt, H.L., Blood parameters indicative of
oxidative stress are associated with symptom expression in chronic fatigue syndrome, Redox Report
(2000); 5 (1): 35-41.
36. Fulle, S., Mecocci, P., Fano, G., Vecchiet, I., Vecchini, A., Racciotti, D., Cherubini, A., Pizzigallo, E.,
Vecchiet, L., Senin, U., and Beal, M.F., Specific oxidative alterations in vastus lateralis muscle of patients
with the diagnosis of chronic fatigue syndrome, Free Radical Biol. and Med. (2000); 29 (12): 1252-1259.
37. Manuel y Keenoy, B., Moorkens, G., Vertommen, J., and De Leeuw, I., Antioxidant status and lipoprotein
peroxidation in chronic fatigue syndrome, Life Sciences (2001); 68: 2037-2049.
38. Vecchiet, J., Cipollone, F., Falasca, K., Mezzetti, A., Pizzigallo, E., Bucciarelli, T., De Laurentis, S., Affaitati,
G., De Cesare, D., Giamberardino, M.A., Relationship between musculoskeletal symptoms and blood
markers of oxidative stress in patients with chronic fatigue syndrome, Neuroscience Letts. (2003); 335:
151-154.
39. Smirnova, I.V., and Pall, M.L., Elevated levels of protein carbonyls in sera of chronic fatigue syndrome
patients, Molecular and Cellular Biochem. (2003); 248: 93-95.
40. Jammes, Y., Steinberg, J.G., Mambrini, O., Bregeon, F., and Delliaux, S., Chronic fatigue syndrome:
assessment of increased oxidative stress and altered muscle excitability in response to incremental
exercise, J. Intern. Med. (2005); 257 (3): 299-310.
41. Maes, M., Mihaylova, I. and Leunis, J.C., Chronic fatigue syndrome is accompanied by an IgM-related
immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and
proteins, Neuro Endocrinol. Lett. (2006); 27 (5): 615-621.
References (continued)
42. Richards, R.S., Wang, L., and Jelinek, H., Erythrocyte oxidative damage in chronic fatigue syndrome,
Arch. Med. Res. (2007); 38 (1): 94-98.
43. Maes, M., Mihaylova, I., and Bosmans, E., Not in the mind of neurasthenic lazybones but in the cell
nucleus: patients with chonic fatigue syndrome have increased production of nuclear factor kappa beta,
Neuro Endocrinol. Lett. 28(4), 456-462 (2007).
44. Spence, V.A., Kennedy, G., Belch, J.J., Hill, A., and Khan, F., Low grade inflammation and arterial wave
reflection in patients with chronic fatigue syndrome, Clin. Sci. (Lond.) (2007) Nov. 21 [Epub ahead of
print].
45. Dunstan,R.H., Donohoe, M., Taylor, W., Roberts, T.K., Murdoch, R.N., Watkins, J.A., and McGregor, N.R., A
preliminary investigation of chlorinated hydrocarbons and chronic fatigue syndrome, Med J Aust 1995
Sep 18;163(6):294-7.
46. Racciatti, D., Vecchiet, J., Ceccomancini, A., Ricci, F., and Pizzigallo, E., Chronic fatigue syndrome
following a toxic exposure, Sci Total Environ. 2001 Apr 10;270(1-3):27-31.
47. Nogue, S., Fernandez-Sola, J., Rovira, E., Montori, E., Fernandez-Huerta, J.M. and Munne, P., Multiple
chemical sensitivity: study of 52 cases, Med Clin (Barc). 2007 Jun 16;129(3):96-8; quiz 99.
48. Lindh, U., Hudecek, R., Danersund, A., Eriksson, S., Lindvall, A., Removal of dental amalgams and other
metal alloys supported by antioxidant therapy alleviates symptoms and improves quality of life in patients
with amalgam-associated ill health, Neuro Endocrinol Lett. 2002 Oct-Dec;23(5-6):459-82.
References (continued)
49. Watson, W.P., Munter, T. and Golding, B.T., A new role for glutathione: protection of vitamin B12 from
depletion by xenobiotics, Chem. Res. Toxicol. 17: 1562-1567 (2004).
50. Deth, R., Muratore, C., Benzecry, J., Power-Charnitsky, V.A., and Waly, M., How environmental and genetic
factors combine to cause autism: A redox/methylation hypothesis, Neurotoxicology. 2008 Jan;29(1):190
201.
51. DeSimone R.E., Penley, M.W., Charbonneau, L, Smith, S.G., Wood, J.M., Hill, H.A., Pratt, J.M., Ridsdale, S.,
and Williams, R.J., The kinetics and mechanism of cobalamin-dependent methyl and ethyl transfer to
mercuric ion, Biochim Biophys Acta 1973 May 28;304(3):851-63.
52. Waly, M., Olteanu, H., Banerjee, R., Choi, S-W., Mason, J.B., Parker, B.S., Sukumar, S., Shim, S., Sharma,
A., Benzecry, J.M., Power-Charnitsky, V-A., and Deth, R.C., Activation of methionine synthase by insulin
like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal, Molec
Psychiatry. 2004, Apr;9(4):358-70.
53. Stipanuk, M.H., Sulfur amino acid metabolism: pathways for production and removal of homocysteine and
cysteine, Annu Rev Nutr 24: 539-577 (2004).
54. Stipanuk, M.H., and Beck, P.W., Characterization of the enzymatic capacity for cysteine desulfhydration in
liver and kidney of rat, Biochem J 206: 267-277 (1982).
55. Carlo-Stella, N., Badulli, C., De Silvestri, A., Bazzichi, L., Martinetti, M., Lorusso, L., Bombardieri, S.,
Salvaneschi, L., and Cuccia, M., A first study of cytokine genomic polymorphisms in CFS: positive
association of TNF-857 and IFNgamma 874 rare alleles, Clin. Exp. Rheumatol. (2006); 24 (2): 179-182.
References (continued)
56. Smith, A.K., White, P.D., Aslakson, E., Vollmer-Conna, U., and Rajeevan, M.S., Polymorphisms in genes
regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue,
Pharmacogenomics (2006); 7 (3): 387-394.
57. Goertzel, B.N., Pennachin, C., Coelho, L. de S., et al., Combinations of single nucleotide polymorphisms in
neuroendocrine effector and receptor genes predict chronic fatigue syndrome, Pharmacogenomics
(2006); 7 (3): 475-483.
58. Narita, M., Nishigami, N., Narita, N., Yamaguti, K., Okado, N., Watanabe, Y., and Kuratsune, H., Association
between serotonin transporter gene polymorphism and chronic fatigue syndrome, Biochem. Biophys.
Res. Commun. (2003); 311 (2): 264-266.
59. Vladutiu, G.D., and Natelson, B.H., Association of medically unexplained fatigue with ACE
insertion/deletion polymorphism in Gulf War veterans, Muscle Nerve 30(1): 38-43 (2004).
60. Torpy, D.J., Bachmann, A.W., Gartside, M., Grice, J.E., Harris, J.M., Clifton, P., Easteal, S., Jackson, R.V.,
Whitworth, J.A., Association between chronic fatigue syndrome and the corticosteroid-binding globulin
gene ALA SER224 polymorphism, Endocr. Res. (2004); 30 (3): 417-429.
61. Rajaveen, M.S., Smith, A.K., Dimulescu, I., Unger, E.R., Vernon, S.D., Heim, C., and Reeves, W.C.,
Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome,
Genes Brain Behav. (2007), 6:167-176,
62. Peckerman, A., LaManca, J.J., Dahl, K.A., Chemitiganti,R., Qureishi, B., and Natelson, B.H., Abnormal
impedance cardiography predicts symptom severity in chronic fatigue syndrome, Am. J. Med. Sci.
(2003);326(2):55-60.
References (continued)
63. Skowera, A., Cleare, A., Blair, D., Bevis, L., Wessely, S.C., and Peakman, M., High levels of type 2 cytokine
producing cells in chronic fatigue syndrome, Clin. Exp. Immunol. (2004) 135:294-302.
64. Maher, K.J., Klimas, N.G., and Fletcher, M.A., Immunology, chapter 7 in Handbook of Chronic Fatigue
Syndrome (2003), L.A. Jason, P.A. Fennell, and R.R. Taylor, eds., Wiley, Hoboken, NJ, pp. 124-151.
65. Komaroff, A.L., and Buchwald, D.S., Chronic fatigue syndrome: an update, Annual Reviews of Medicine
(1998) 49:1-13.
66. Wikland, B., Lowhagen, T., and Sandberg, P.O.. Fine-needle aspiration cytology of the thyroid in chronic
fatigue, Lancet (2001); 357 (9260): 956-957.
67. Chakravarthi, S., and Bulleid, N.J., Glutathione is required to regulate the formulation of native disulfide
bonds within proteins entering the secretory pathway, J Biol Chem (2004); 279(38): 39872-39879.
68. Demitrack, M.A., Dale, J.K., Straus, S.E., Laue, L., Listwak, S.J., and Kruesi, M.J., Evidence for
impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome,
J. Clin. Endocrinol. Metab. (1991); 73(6): 124 1234.
69. Bakheit, A.M., Behan, P.O., Watson, W.S., and Morton, J.J., Abnormal arginine-vasopressin secretion and
water metabolism in patients with postviral fatigue syndrome, Acta Neurol. Scand. (1993); 87 (3): 234-238.
70. Maher, K.J., Klimas, N.G. and Fletcher, M.A., Chronic fatigue syndrome is associated with diminished
intracellular perforin, Clin. Exp. Immunol. (2005); 142 (3): 505-511.
References (continued)
71. Kerr, J., Burke, B., Petty, R., Gough, J., Fear, D., David, M., Axford, J., Dalgleish, A., and Nutt, D., Seven
genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a detailed analysis
of gene networks and clinical phenotypes, J. Clin. Pathol. published online 5 Dec 2007; doi:
10.1136/jcp.2007.053553.
72. Tomoda, A., Miike, T., Yamada, E., Honda, H., Moroi, T., Ogawa, M., Ohtani, Y., and Morishita, S., Chronic
fatigue syndrome in childhood, Brain & Development (2000); 22: 60-64.
73. Puri, B.K., Counsell, S.J., Saman, R., Main, J., Collins, A.G., Hajnal, J.V. and Davey, N.J., Relative increase
in choline in the occipital cortex in chronic fatigue syndrome, Acta Psychiatr. Scand. (2002); 106: 224-226.
74. Chaudhuri, A., Condon, B.R., Gow, J.W., Brennan, D. and Hadley, D.M., Proton magnetic resonance
spectroscopy of basal ganglia in chronic fatigue syndrome, NeuroReport 2003; 14 (2): 225-228.
75. Levine,S., Cheney, P., Shungu, D.C., and Mao, X., Analysis of the metabolic features of chronic fatigue
syndrome (CFS) using multislice 1H MRSI, abstract, conference syllabus, Seventh Intl. AACFS Conference
on Chronic Fatigue Syndrome, Fibromyalgia and Other Related Illnesses, Madison, WI, U.S.A., October 8
10, 2004.
76. Kuratsune, H, Yamaguti, K, Takahashi, M., Misaki, H., Tagawa, S., and Kitani, T., Acylcarnitine deficiency in
chronic fatigue syndrome, Clinical Infectious Diseases (1994); 18(Suppl.): S62-S67.
77. Langsjoen, P.H., Langsjoen, P.H. and Folkers, K., Clin. Investig. (1993); 71(8 Suppl): S140-S144.
78. Michiels, V., and Cluydts, R., Neuropsychological functioning in chronic fatigue syndrome: a review, Acta
Psychiatr Scand. 2001 Feb;103(2):84-93.
Folate metabolism