![[Co-Cure ME/CFS & Fibromyalgia Information Exchange Forum Logo]](cc2b5.gif)
Co-Cure Weekly Digest of research and medical posts only - 15 Jan 2007 to 22 Jan 2007
Topics of the week:
2. RES: Fibromyalgia. Diagnostics - Disease Approach - Therapy
3. RES,NOT: Small trial stirs hope for PWCs
4. RES: Ca(2+) channel alpha(2)delta ligands: novel modulators of neurotransmission
5. RES: Why is the prevalence of chronic fatigue syndrome higher in women than in men?
7. RES: Growth Hormone Perturbations in Fibromyalgia: A Review
9. MED: The Role of Infection in Initiating ME/CFS
10. RES,NOT,URL: ME-NET will move soon
11. RES, MED, ACT, NOT: CDs and DVDs of the recent IACFS conference are available
12. RES: Sensitivity disturbances in patients with irritable bowel syndrome and fibromyalgia
13. RES,NOT: CDC launches First-Ever CFS Awareness Campaign
14. RES: CFS/ME & FM papers, published since December 2006
15. NOT,RES: An informal IACFS conference summary - first take
1. RES: A Pilot Study of the Efficacy of Heart Rate Variability (HRV) Biofeedback in Patients with Fibromyalgia
[Return to digest index]
---------------------------------------------
This is a special digest of
Co-Cure Research & Medical posts only
Problems? Write to mailto:mods@co-cure.org
---------------------------------------------
----------------------------------------------------------------------
Date: Tue, 16 Jan 2007 14:39:30 -0500
From: "Bernice A. Melsky" <bernicemelsky verizon.net>
Subject: RES: A Pilot Study of the Efficacy of Heart Rate Variability (HRV) Biofeedback in Patients with Fibromyalgia
A Pilot Study of the Efficacy of Heart Rate Variability (HRV) Biofeedback
in Patients with Fibromyalgia.
Appl Psychophysiol Biofeedback. 2007 Jan 12; [Epub ahead of print]
Hassett AL, Radvanski DC, Vaschillo EG, Vaschillo B, Sigal LH, Karavidas
MK, Buyske S, Lehrer PM.
Department of Medicine, Division of Rheumatology, University of Medicine
and Dentistry of New Jersey, Robert Wood Johnson Medical School
(UMDNJ-RWJMS), P.O. Box 19, MEB-484, New Brunswick, NJ, USA, <a.hassett umdnj.edu>.
PMID: 17219062
Fibromyalgia (FM) is a non-inflammatory rheumatologic disorder
characterized by musculoskeletal pain, fatigue, depression, cognitive
dysfunction and sleep disturbance. Research suggests that autonomic
dysfunction may account for some of the symptomatology of FM. An open label
trial of biofeedback training was conducted to manipulate suboptimal heart
rate variability (HRV), a key marker of autonomic dysfunction.
Methods: Twelve women ages 18-60 with FM completed 10 weekly sessions of
HRV biofeedback. They were taught to breathe at their resonant frequency
(RF) and asked to practice twice daily. At sessions 1, 10 and 3-month
follow-up, physiological and questionnaire data were collected.
Results: There were clinically significant decreases in depression and pain
and improvement in functioning from Session 1 to a 3-month follow-up. For
depression, the improvement occurred by Session 10. HRV and blood pressure
variability (BPV) increased during biofeedback tasks. HRV increased from
Sessions 1-10, while BPV decreased from Session 1 to the 3 month follow-up.
Conclusions: These data suggest that HRV biofeedback may be a useful
treatment for FM, perhaps mediated by autonomic changes. While HRV effects
were immediate, blood pressure, baroreflex, and therapeutic effects were
delayed. This is consistent with data on the relationship among stress, HPA
axis activity, and brain function.
[Return to top]
------------------------------
Date: Tue, 16 Jan 2007 14:42:16 -0500
From: "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Fibromyalgia. Diagnostics - Disease Approach - Therapy
[Fibromyalgia. Diagnostics - Disease Approach - Therapy.]
[Article in German]
Med Klin (Munich). 2007 Jan;102(1):23-29.
Lakomek HJ, Lakomek M, Bosquet-Nahrwold K.
Klinik fur Rheumatologie und Physikalische Medizin, Klinikum Minden,
Friedrichstrasse 17, 32427, Minden, Deutschland, <rheumatologie klinikum-minden.de>.
PMID: 17221348
Fibromyalgia is a complex of symptoms predominantly affecting females and
consisting of widespread pain.Etiology and pathogenesis are not
sufficiently known yet, however, there is the assumption that fibromyalgia
is looked at as being an illness with biological, psychological, and social
aspects. Therefore, the treatment of fibromyalgia calls for a multimodal
therapy approach.
The importance of fibromyalgia has been recognized within the German health
system by creating the new ICD code M79.70 and by assigning fibromyalgia
its own rheumatologic DRG (I79Z).In future research of fibromyalgia special
attention needs to be placed upon gender-specific problems.
[Return to top]
------------------------------
Date: Tue, 16 Jan 2007 23:34:35 +0100
From: "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: Small trial stirs hope for PWCs
Source: Scientific American
Date: January 14, 2007
Author: Toni Clarke
URL: http://www.sciam.com/article.cfm?chanID=sa003&articleID=BBFAC18D2EDB930651D866F44FCFCB62
Small trial stirs hope for chronic fatigue patients
---------------------------------------------------
BOSTON (Reuters) - Shortly after hiking the Grand Canyon with his wife in
1988, Michael Manson, the co-founder of PetSmart Inc., came down with what
felt like the flu. So did business partner Jim Dougherty. The illness changed
their lives.
In both men, the flu-like symptoms triggered a more debilitating condition
known as chronic fatigue syndrome for which there is no known cure, and no
known cause. Its symptoms range from fatigue and vertigo to nausea, pain and
cognitive confusion.
Many in the medical community don't believe chronic fatigue syndrome is a real
disease. There is no diagnostic test for it. Patients are often referred to
psychiatrists on the assumption that their symptoms are psychosomatic.
But for those who suffer its symptoms, including Manson and Dougherty, a
former marine who served twice in Vietnam, the condition is all too
devastatingly real.
"We've been fighting this for 18 years, and we've tried every possible
treatment, from wing of bat to eye of newt," said Manson, who has spent months
at a time too weak to walk more than a block or even get out of bed.
Nothing worked - until now.
Last June, Manson went to see Dr. Jose Montoya, associate professor of
medicine at Stanford University and a specialist in infectious diseases who
believes the disorder may be caused - at least in some cases, by one or more
viruses.
Montoya had presented anecdotal data earlier that year at a conference in
Barcelona, Spain, which suggested an antiviral drug called Valcyte, made by
Swiss drugmaker Roche Holding AG, could be helpful in treating certain CFS
patients.
Montoya now has data on 25 CFS patients, nearly all of whom had high levels in
their blood plasma of antibodies to the human herpes virus 6 (HHV-6) and the
Epstein-Barr virus.
The data - presented recently at a conference in Fort Lauderdale, Florida -
were remarkably consistent. Nearly every patient responded to the drug,
Montoya said, and most of the responses were dramatic.
"Scientists have suspected viruses for years but have never been able to prove
it," said Kristin Loomis, executive director of the HHV-6 Foundation, a
non-profit group which funds research into HHV-6.
Last year Manson began a six-month course of Valcyte, which is approved to
treat transplant patients to prevent viral infection. At first he felt worse.
Then, after a few weeks, he began to improve. He started walking, every day a
little more.
Now, nearly seven months later, he is walking two or three miles a day and
working out with light weights. And he is working on new business ideas.
"Not only is my physical ability returning but my cognitive ability has come
back too," Manson said.
Even so, Montoya stresses that the study is extremely small and the results
may not be replicated in bigger trials, the first of which he hopes to start
within the next few months.
"In a field that has been so stigmatized, and so full of false hopes, I think
the patients and the field deserve the best kind of trial, keeping an open
mind to the possibility that it won't work," he said.
Roche has agreed to put up $1.5 million to fund the next, 30-patient study
"Whether we put serious money behind this will all depend on the outcome of
this next study," said Nigel Pluck, Roche's clinical science leader for
Valcyte. "This is a somewhat contentious area for the medical profession in
that CFS is not a disease that you can test for. It's a diagnosis that you
come to by excluding everything else."
Even if results of further studies are positive they will probably apply only
to those patients with active HHV-6 and Epstein-Barr viruses, as indirectly
measured by the number of antibodies produced to fight them, Montoya said.
But for those who appear to fit the profile, like Manson, the benefits could
be enormous. "We are very excited and holding our breath," he said.
--------
(c) 2007 Scientific American
[Return to top]
------------------------------
Date: Wed, 17 Jan 2007 12:45:07 -0500
From: "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Ca(2+) channel alpha(2)delta ligands: novel modulators of neurotransmission
Ca(2+) channel alpha(2)delta ligands: novel modulators of neurotransmission.
Trends Pharmacol Sci. 2007 Jan 9; [Epub ahead of print]
Dooley DJ, Taylor CP, Donevan S, Feltner D.
Department of CNS Pharmacology, Pfizer Global Research and Development, Ann
Arbor, MI 48105, USA.
PMID: 17222465
The term 'Ca(2+) channel alpha(2)delta ligands' has recently been applied
to an evolving drug class that includes gabapentin (Neurontin((R))) and
pregabalin (Lyrica((R))), and reflects significant progress over the past
decade in elucidating the mechanism of action of these drugs: a novel,
specific action at one of the subunits constituting voltage-sensitive
Ca(2+) channels.
Binding of these ligands to the alpha(2)delta subunit is considered to
explain their usefulness in treating several clinical disorders, including
epilepsy, pain from diabetic neuropathy, postherpetic neuralgia and
fibromyalgia, and generalized anxiety disorder.
The evidence indicates a relationship between alpha(2)delta subunit binding
and the modulation of processes that subserve neurotransmission. This
modulation is characterized by a reduction of the excessive
neurotransmitter release that is observed in certain neurological and
psychiatric disorders.
[Return to top]
------------------------------
Date: Thu, 18 Jan 2007 14:23:10 -0500
From: "Richard A Van Konynenburg PhD <richvank aol.com> via Co-Cure
Moderators"
Subject: RES: Why is the prevalence of chronic fatigue syndrome higher in women than in men?
WHY IS THE PREVALENCE
OF CHRONIC FATIGUE SYNDROME
HIGHER IN WOMEN THAN IN MEN?
by
Richard A Van Konynenburg, Ph.D.
(Independent Researcher and Consultant)
8th International IACFS Conference on
Chronic Fatigue Syndrome, Fibromyalgia
and other Related Illnesses
Ft. Lauderdale, Florida, U.S.A.
January 10-14, 2007
Epidemiological studies have found that the prevalence of CFS is
significantly higher in women than in men.
Jason et al. (1) found a ratio of 1.8 (women to men) in a community-based
study in Chicago, IL, USA, that included over 28,000 adults.
Reyes et al. (2) found a ratio of 4.5 (women to men) in a study in Wichita,
KN, USA, that included nearly 24,000 households.
Other studies in San Francisco, CA, USA (3), the U.K. (4), Australia (5),
Sweden (6), Iceland (7) and the Netherlands (8) have also found
significantly higher prevalence of CFS or CFS-like illness in women.
Children have been found to have a lower rate of incidence of CFS than
adults, and there does not appear to be an effect of gender on the
incidence of CFS in childhood:
Carter and Marshall (1995) (9)
Jordan et al. (2000) (10)
Chalder et al. (2003) (11)
Means et al. (2004) (12)
Jones et al. (2004) (13)
Farmer et al. (2004) (14)
ter Wolbeek et al. (2006) (15)
This suggests that the transition to a higher relative rate of incidence of
CFS in females occurs during adolescence, and thus that it may be related
to increases in production of the female sex hormones, which occur at that
time.
Hypothesis
1. Many people with CFS have polymorphisms in the genes that code for the
detox enzymes that metabolize the estrogens, and in particular the dominant
estrogen, estradiol.
2. These polymorphisms can be expected to occur equally in males and
females, since these genes are autosomal (i.e. they are located on non-sex
chromosomes). However, these polymorphisms would be particularly important
in women who are in their potentially reproductive years, because of the
higher production of estradiol in these women.
3. One result of the presence of these polymorphisms would be to increase
the levels of semiquinones and quinones (16).
4. Semiquinones and quinones react back and forth between each other in a
process that generates superoxide ions and is called redox cycling (17).
5. This redox cycling would produce an additional contribution to
oxidative stress in these women that does not occur in men. Men's bodies
produce much lower amounts of estradiol (by the action of aromatase on
testosterone), and the metabolism of the remainder of the testosterone
occurs by different pathways that do not involve redox cycling (18).
6. According to the Glutathione DepletionMethylation Cycle Block
Hypothesis for the pathogenesis of CFS (19), oxidative stress depletes
glutathione, which leads to the onset of CFS.
7. Therefore, women in their potentially reproductive years who have the
relevant polymorphisms would have an additional factor biasing them toward
onset of CFS that men do not have, and this would produce a higher
prevalence of CFS in women than in men.
(Note that this redox cycling mechanism is well established and has been
under study for several years because of its possible involvement in
carcinogenesis (16, 17).
Rates of Production of Estradiol in
Males and Females
PREPUBERTAL CHILDREN (20, 21):
BOYS: 0.04 micrograms per day
GIRLS: 0.3 micrograms per day
MEN: 50 micrograms per day (22)
WOMEN (by menstrual cycle stage) (22):
Early follicular 36 micrograms per day
Preovulatory 380 micrograms per day
Midluteal 250 micrograms per day
Normal Metabolism of Estradiol by Detox Enzymes (23,24)
(See diagram http://www.co-cure.org/scan0004.bmp )
The metabolism of estradiol (and of the estrogens in general) is complex,
including a large number of alternative pathways and metabolites.
Most of the metabolism of estradiol occurs in the liver, while smaller
amounts occur in other organs, including breast, uterus, brain, kidneys and
ovaries.
Some estradiol is converted to estrone, and some is acted upon by various
CYP450 enzymes to form multiple hydroxylated metabolites. Estradiol
itself, estrone and these hydroxylated metabolites can be conjugated by
other detox enzymes to form sulfates, glucuronides, or fatty acid
esters. The various sulfate and glucuronide conjugates are the main
metabolites that are excreted in urine and stools. Only the major pathways
of estradiol metabolism are discussed in detail in the following.
The main hydroxylation reactions in the liver involve the CYP450 enzymes
CYP3A and CYP1A2, and their chief product is 2-hydroxyestradiol, which is a
catechol estradiol.
A smaller fraction of the total estradiol is metabolized by the enzyme
CYP1B1, located in organs other than the liver. This reaction primarily
produces 4-hydroxyestradiol, another catechol estradiol.
Most of the catechol estradiols are O-methylated by the enzyme
catechol-O-methyltransferase (COMT) to form 2- and 4-methoxyestradiols,
which are excreted.
Some of the catechol estradiol molecules escape the COMT reaction and
instead are further oxidized by CYP1B1 to form semiquinones, which in turn
are oxidized to form quinones. Normally, these are conjugated to
glutathione by the glutathione transferase (GST) superfamily of enzymes and
are excreted.
What would happen to estradiol metabolism if there were polymorphisms in
the detox enzymes?
(See diagram http://www.co-cure.org/scan0004.bmp )
CYP3A4 AND CYP1A2: Known polymorphisms that lower the activity of these
enzymes would decrease the fraction of estradiol that is metabolized by
them in the liver. This would have the effect of increasing the fraction
of estradiol that is metabolized in other organs by CYP1B1.
CYP1B1: Known polymorphisms that raise its activity would cause a greater
rate of production of 4-hydroxyestradiol, and would also cause more of this
to be oxidized to form semiquinones and quinones (16).
COMT: Known polymorphisms that lower its activity would decrease the
fraction of 4-hydroxyestradiol that is methylated, leaving more to be
oxidized to semiquinones and quinones.
GST enzymes: Known polymorphisms that lower the activity of members of
this superfamily of enzymes would decrease the rate of removal of
semiquinones and quinones, leaving more of them to carry on redox cycling
and to contribute to oxidative stress (25).
Have any of the detox enzymes that metabolize estradiol been found to have
these polymorphisms at higher frequencies in people with CFS?
Of these enzymes, so far the only one that has been reported to have been
studied in CFS is COMT.
Goertzel et al. (26) found that they could distinguish CFS cases from
controls with an accuracy of 75% by using combinations of polymorphisms of
only five genes. They reported that of the nine genes containing a total
of 28 polymorphisms that they considered, the gene for COMT was among the
three most important genes for distinguishing CFS cases from
controls. They considered six COMT polymorphisms in their study. (This
result is remarkable in view of the facts that the entire human genome
contains about 25,000 genes and several million polymorphisms, and this
demonstrates the importance of elevated frequencies of COMT polymorphisms
in CFS.)
Two studies (27,28) have found the COMT Val 158 Met polymorphism to have
significantly higher frequencies in people with fibromyalgia than in
controls. (This may be relevant because of the high comorbidity between
CFS and fibromyalgia.)
What about polymorphisms in the CYP and GST enzymes in CFS? Have they been
observed at elevated frequencies?
Although no studies have yet been published about the frequencies of
polymorphisms in the CYP enzymes or the glutathione transferases in CFS
relative to controls, the author has received anecdotal reports from
several people with CFS who have had these polymorphisms characterized, and
trends in the data suggest high frequencies for these polymorphisms in CFS,
also.
Conclusions
This hypothesis is consistent with known biochemistry, and in combination
with the Glutathione DepletionMethylation Cycle Block Hypothesis for the
pathogenesis of chronic fatigue syndrome (19), it provides a plausible
explanation for the observed higher prevalence of CFS in women, a feature
that has heretofore not been explained.
This hypothesis is also consistent with available evidence concerning the
elevated frequencies of polymorphisms in catechol-O-methyltransferase
(COMT) in CFS.
Controlled study in people with CFS of the frequencies of polymorphisms in
the other enzymes involved in the metabolism of estradiol appears to be
warranted. Such study would test this hypothesis. It would also shed
light on the pathogenesis of CFS, and perhaps on the pathogeneses of other
disorders important in women's health.
References
1. Jason, L.A., Richman, J.A., Rademaker, A.W. et al., A community-based
study of chronic fatigue syndrome, Arch. Intern. Med. 159 (18), 2129-2137
(1999).
2. Reyes, M., Nisenbaum, R., Hoaglin, D. et al., Prevalence and incidence
of chronic fatigue syndrome in Wichita, Kansas, Arch. Intern. Med. 163,
1530-6 (2003).
3. Steele, L., Dobbins, J.G., Fukuda, K. et al., The epidemiology of
chronic fatigue syndrome in San Francisco, Am. J. Med. 105 (3A), 83S-90S
(1998).
4. Gallagher, A.M., Thomas, J.M., Hamilton, W.T. and White, P.D.,
Incidence of fatigue symptoms and diagnoses presenting in UK family care
from 1990 to 2001, J. Royal. Soc. Med. 97, 571-5 (2004).
5. Lloyd, A.R., Hickie, I., Boughton, C.R. et al., Prevalence of chronic
fatigue syndrome in an Australian population, Med. J. Australia 153, 522-8
(1990).
6. Evengard, B., Jacks, A., Pedersen, N. and Sullivan, P.F., The
epidemiology of chronic fatigue in the Swedish Twin Registry, Psych. Med.
35, 1317-26 (2005).
7. Lindal, E., Stefansson, J.G., and Bergmann, S., The prevalence of
chronic fatigue syndrome in Icelanda national comparison by gender drawing
on four different criteria, Nordic J. of Psychiatry 56 (4), 273-7 (2002).
8. Bazelmans, E., Vercoulen, J.H., Galama, J.M. et al., Prevalence of
chronic fatigue syndrome and primary fibromyalgia syndrome in the
Netherlands, Ned. Tijdschr. Geneeskd. 141 (31), 1520-3 (1997).
9. Carter, B.D. and Marshall, G.S., New developments: diagnosis and
management of chronic fatigue in children and adolescents, Current Problems
in Pediatrics 25, 281-93 (1995).
10. Jordan, K.M., Ayers, P.M., Jahn, S.C. et al., Prevalence of fatigue
syndrome-like illness in children and adolescents, J. Chronic Fatigue
Syndrome 6 (1), 3-21 (2000).
11. Chalder, T., Goodman, R., Wessely, S. et al., Epidemiology of chronic
fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year
olds; cross sectional study, BMJ 327, 654-5 (2003).
12. Mears, C.J., Taylor, R.R., Jordan, K.M. and Binns, H.J.,
Sociodemographic and symptom correlates of fatigue in an adolescent primary
care sample, J. Adolesc. Health 35, 528.e21-528.e26 (2004).
13. Jones, J.F., Nisenbaum, R., Solomon, L. et al., Chronic fatigue
syndrome and other fatiguing illnesses in adolescents: a population-based
study, J. Adolesc. Health 35 (1), 34-40 (2004).
14. Farmer, A., Fowler, T., Scourfield, J., and Thapar, A., Prevalence of
chronic disabling fatigue in children and adolescents, Brit. J. Psychiat.
184, 477-81 (2004).
15. ter Wolbeek, M., van Doornen, L.J., Kavelaars, A., and Heijnen, C.J.,
Severe fatigue in adolescents: a common phenomenon?, Pediatrics 117 (6),
e1078-86 (2006).
16. Sissung, T.M., Price, D.K., Sparreboom, A. and Figg, W.D.,
Pharmacogenetics and regulation of human cytochrome P450 1B1: implications
in hormone-mediated tumor metabolism and a novel target for therapeutic
intervention, Mol. Cancer. Res. 4 (3), 135-50 (2006).
17. Liehr, J.G. and Roy, D., Free radical generation by redox cycling of
estrogens, Free Radical Biol. & Med. 8, 415-23 (1990).
18. Bhagavan, N.V., Medical Biochemistry, fourth edition, Harcourt/Academic
Press, Burlington, MA (2002) pp. 785-6.
19. Van Konynenburg, R.A., Glutathione depletionmethylation cycle block
hypothesis for the pathogenesis of chronic fatigue syndrome, poster paper,
this Conference.
20. Klein, K.O., Baron, J., Colli, M.J. et al., Estrogen levels in
childhood determined by an ultrasensitive recombinant cell bioassay, J.
Clin. Invest. 94, 2475-80 (1994).
21. Andersson, A.M. and Skakkebaek, N.E., Exposure to exogenous estrogens
in food: possible impact on human development and health, Eur. J.
Endocrin. 140, 477-85 (1999).
22. Yen, S.S.C., Jaffe, R.B. and Barbieri, R.L., Reproductive
endocrinology, 4th ed. Saunders (1999), as cited in Ganong, W.F., Review of
medical physiology, twenty-second edition, New York, Lange Medical
Books/McGraw-Hill (2005), p. 441.
23. Tsuchiya, Y., Nakajima, M. and Yokoi, T., Cytochrome P450-mediated
metabolism of estrogens and its regulation in human, Cancer Letts. 227,
115-24 (2005).
24. Raftogianis, R., Creveling, C., Weinshilboum, R., and Weisz, J.,
Chapter 6: Estrogen metabolism by conjugation, J. Nat. Cancer Inst.
Monographs No. 27, 113-24 (2000).
25. Hachey, D.L, Dawling, S., Roodi, N. and Parl, F.F., Sequential action
of phase I and II enzymes cytochrome P450 1B1 and glutathione S-transferase
P1 in mammary estrogen metabolism, Cancer Res. 63, 8492-9 (2003).
26. 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 7 (3), 475-83 (2006).
27. Gursoy, S., Erdal, E., Herken, H. et al., Significance of
catechol-O-methyltransferase gene polymorphism in fibromyalgia, Rheumatol.
Intl. 23, 104-7 (2003).
28. Garcia-Fructuoso, F.J., Beyer, K., and Lao-Villadoniga, J.I., Analysis
of Val 159 Met genotype polymorphisms in the COMT locus and correlation
with IL-6 and IL-10 expression in fibromyalgia syndrome, J. Clin. Res. 9,
1-10 (2006).
[Return to top]
------------------------------
Date: Thu, 18 Jan 2007 15:01:27 -0500
From: "Richard A Van Konynenburg PhD <richvank aol.com> via Co-Cure Moderators"
Subject: RES: Glutathione Depletion--Methylation Cycle Block: A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome
GLUTATHIONE DEPLETION--METHYLATION CYCLE BLOCK:
A HYPOTHESIS FOR THE PATHOGENESIS OF CHRONIC FATIGUE SYNDROME
by
Richard A Van Konynenburg, Ph.D.
(Independent Researcher and Consultant)
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
