Possible Genetic Dysregulation in Pediatric CFS - Jason, Mikovits et. al.

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I did a quick search and couldn't find a discussion on this one.

Possible Genetic Dysregulation in Pediatric CFS

Leonard A. Jason, Matthew Sorenson, Nicole Porter, Molly Brown, Athena Lerch, Constance Van der Eb, Judy Mikovits

ABSTRACT

Hypocortisolism is a frequent finding in individuals with chronic fatigue syndrome (CFS) and could play an explanatory role in the development of illness symptomatology. The etiologic mechanism behind this finding could be genetic variance in glucocorticoid receptor expression (GR) or increased resistance to the effects of glucocorticoids. Several investigators believe that allelic variance in a GR (NR3C1) mediates the expression of chronic fatigue possibly through influence on hypothalamic-pituitary-adrenal (HPA) axis function [1]. In addition, several immunologic variables are associated with CFS. The nuclear factor kappa beta (NFkB) pathway is heavily involved in cellular transcription and regulation and has been shown to be associated with the development of CFS. The NFkB pathway is directly regulated by and influences the presence of GR [2]. Our study focused on assessing whether such inflammatory transcription is occurring during adolescent years. Findings indicated decreased expression of NFKB1, NFKB2, and NR3C1. A decrease in the expression of these genes may have effects on immune cell function and cytokine production that could explain immunologic findings seen in individuals with CFS.
http://www.scirp.org/journal/PaperInformation.aspx?paperID=3046&JournalID=148
PDF: http://www.scirp.org/journal/PaperDownload.aspx?FileName=Psych.20100400004_58674684.pdf&paperID=3046
 

WillowJ

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1) why on earth are they citing Rajeevan et al.'s glucocorticoid study as if Reeves disease had some relevance?? These scientists know better than that :confused: Maybe because of NAID grant? ... other bogus citations :headdesk: :headdesk: :confused: ... and a few fine citations...

Ok, big deal over small potatoes, it's the introduction, I know. They're supposed to cite the other literature. But...

2) ok, that's amusing... they define apoptosis for their audience? or did they know a lay audience would be reading and do it for their benefit? (question for those with no training in higher science: does "programmed cell death" mean anything to you anyway?)

3) wait, they did not characterize their CFS population, other than location, age, and race. No definition, no length of time ill, no level of disability, no presence/absence of depression, no nothing.

4) they did not characterize the control group, either, except to mention that it was pediatric. Not even location, age, and race. No presence or absence of fatigue (we really should be using other fatiguing medical disease plus healthy persons as dual controls, to check what things are unique to ME and what things go along with chronic disease in general), no nothing.

5) the causative possibilities are multiple but they do include infections, lack heat shock protein (Hsp, a cell repair protein; lack of certain types of Hsp has been found by Jammes et al. and Thambirajah et al.), and oxidative damage.
 
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Well I'm skeptical of the 'neuroendocrine' model of CFS in general, but I thought I'd post this study here for you guys anyway.

An age range for the pediatric (control) samples was given - 6-16.

Most of the studies that I have read measuring salivary cortisol (or serum for that matter) have methodological deficiencies (samples must be taken on days of rest - Saturdays for controls, several samples must be taken over the first hour so that proper compliance can be demonstrated). Such studies should also use individuals with other chronic diseases with similar activity patterns as controls.
Otherwise low cortisol and glucocorticoid gene expression could have a much simpler explanation - CFS patients lead lower stress lifestyles (due to low activity, no school/employment etc).

It is possible that this model may only explain the symptoms of a subset of patients - you can't analyse the distribution with such a small sample though.

The hypothetical mechanisms discussed however are interesting.

This appears to be Sorenson's work:
http://las.depaul.edu/nursing/People/FulltimeFaculty/MatthewSorrenson.asp
 

Dolphin

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1) why on earth are they citing Rajeevan et al.'s glucocorticoid study as if Reeves disease had some relevance?? These scientists know better than that :confused: Maybe because of NAID grant? ... other bogus citations :headdesk: :headdesk: :confused: ... and a few fine citations... .

Ok, big deal over small potatoes, it's the introduction, I know. They're supposed to cite the other literature. But...
I wasn't pleased to see that reference either [or reference 11 which is actually the same data set (Wichita 2-day study) which was analysed by different groups]. But at least this study investigated the issue - it didn't really depend on that reference (like a literature review might).

2) ok, that's amusing... they define apoptosis for their audience? or did they know a lay audience would be reading and do it for their benefit? (question for those with no training in higher science: does "programmed cell death" mean anything to you anyway?)
I stopped studying biology aged 16. I find it useful when researchers give just enough information that somebody without higher training might be able to understand a paper or at least the rationale. I find I can get the jist of lots of papers without fully understanding the biological systems involved.

I have come across the concept of apotosis a few times over the years. But don't mind a little reminder about what it is (which can remind me of a something a little more detailed I read).
 

Dolphin

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Well I'm skeptical of the 'neuroendocrine' model of CFS in general, but I thought I'd post this study here for you guys anyway.
Yes, good to post what is coming out. It's certainly of some interest given the authors. Even if studies themselves aren't always of that much interest to me, it can be interesting to see what direction authors are going, theories they have, etc. from papers.

An age range for the pediatric samples was given - 6-16.
Just to be clear, you're talking about the controls.
Data were collected in the mornings from a sample of
adolescents with CFS (n = 6) which was obtained from
the Chicago metropolitan area. Five were Caucasian and
one Asian-American. Three were female and three were
male. The average age was 17.8 years (range from 16 to
21). All were diagnosed with CFS by a physician who
was familiar with this illness.
Most of the studies that I have read measuring salivary cortisol (or serum for that matter) have methodological deficiencies (samples must be taken on days of rest - Saturdays for controls, several samples must be taken over the first hour so that proper compliance can be demonstrated). Such studies should also use individuals with other chronic diseases with similar activity patterns as controls.
Otherwise low cortisol and glucocorticoid gene expression could have a much simpler explanation - CFS patients lead lower stress lifestyles (due to low activity, no school/employment etc).
Good point.

I have been sceptical of neuroendocrine models in the past. However, it is interesting that some studies have suggested they can be useful to predict responses to nonpharmacological trials.

Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome?

Psychol Med. 2010 Mar;40(3):515-22. Epub 2009 Jul 17.

Roberts AD, Charler ML, Papadopoulos A, Wessely S, Chalder T, Cleare AJ.

King's College London, Institute of Psychiatry, Department of Psychological Medicine, London, UK.

Abstract

BACKGROUND: There is evidence that patients with chronic fatigue syndrome (CFS) have mild hypocortisolism. The clinical significance of this is unclear. We aimed to determine whether hypocortisolism exerted any effect on the response of CFS to cognitive behavioural therapy (CBT).

METHOD: We measured 24-h urinary free cortisol (UFC) in 84 patients with Centers for Disease Control and Prevention (CDC)-defined CFS (of whom 64 were free from psychotropic medication) who then received CBT in a specialist, tertiary out-patient clinic as part of their usual clinical care. We also measured salivary cortisol output from 0800 to 2000 h in a subsample of 56 psychotropic medication-free patients.

RESULTS: Overall, 39% of patients responded to CBT after 6 months of treatment. Lower 24-h UFC output was associated with a poorer response to CBT but only in psychotropic medication-free patients. A flattened diurnal profile of salivary cortisol was also associated with a poor response to CBT.

CONCLUSIONS: Low cortisol is of clinical relevance in CFS, as it is associated with a poorer response to CBT. Hypocortisolism could be one of several maintaining factors that interact in the persistence of CFS.
Jason LA, Torres-Harding S, Maher K, Reynolds N, Brown M, Sorenson M, Donalek J, Corradi K, Fletcher MA, & Lu T (2007). Baseline cortisol levels predict treatment outcomes in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 14, 4, 39-59.

ABSTRACT.
Objective: Understanding how non-pharmacological interventions differentially affect subgroups of patients with CFS might provide insights into the pathophysiology of this illness. In this exploratory study, baseline measures of normal versus abnormal cortisol were compared on a variety of immune markers and other self-report measures.
Normal versus abnormal cortisol ratings were used as predictors in a nurse delivered non-pharmacologic intervention.

Methods: Participants diagnosed with CFS were assigned to 6-month non-pharmacologic interventions. Individuals were classified as having abnormal or normal cortisol levels based on scores over the 5 testing times. Cortisol levels were considered abnormal if they continued to rise, were flat, or were at abnormally low over time.

Results: Across interventions, those with abnormal cortisol at the baseline appeared not to improve over time, whereas those with normal baseline cortisol evidenced improvements on a number of immunologic and self-report measures.

Conclusion: It appears that, in subgroups of individuals with CFS, baseline cortisol markers are associated with outcome trajectories for non-pharmacologic treatment trials. The implications of these findings are discussed.
Of course, other things can predict outcomes also:
Free full text at: http://www.jstage.jst.go.jp/article/tmh/36/1/23/_pdf

Jason LA, Torres-Harding S, Brown M, Sorenson M, Julie D, Corradi K, Maher K, Fletcher MA (2008). Predictors of change following participation in non-pharmacologic interventions for CFS. Tropical Medicine and Health 36, 23-32

The purpose of this study was to evaluate predictors of change in physical function in individuals diagnosed with chronic fatigue syndrome (CFS) following participation in nurse delivered, non-pharmacologic interventions.

Participants diagnosed with CFS were randomly assigned to one of four 6-month interventions including cognitive behavior therapy, cognitive therapy, anaerobic exercise, or a relaxation control group.

Baseline measures including immune function, actigraphy (rest/activity cycle monitoring), time logs, sleep status, and past psychiatric diagnosis significantly differentiated those participants who demonstrated positive change over time from those who did not.

Understanding how patient subgroups differentially respond to non-pharmacologic interventions might provide insights into the pathophysiology of this illness.
Also, I have seen at least one person rush to say she didn't think she had abnormalities in this area because of one saliva test. I wouldn't be convinced that would be enough. Also, average differences don't show up comparing one sample with norms e.g. women could be less tall than men but many women would still be in a 95% C.I. of male heights.
 
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How about this:

Those with more severe symptoms have reduced activity levels.
Those with more severe symptoms are less likely to have successful outcomes from non-pharmacologic treatments.
Activity levels are correlated with salivary and serum cortisol levels. (at least in healthy patients, according to various papers)

Therefore....

Although I agree there is still the possibility that there might be a subset of CFS patients with Addison's-like pathology. It would be interesting to map the distributions of the low cortisol measurements.

I'm just starting to read "The Associations Between Basal Salivary Cortisol and Illness Symptomatology in Chronic Fatigue Syndrome - Torres-Harding et al." now and they cite Hessen et al who found that low cortisol levels were correlated with cognitive impairment in 15 MS patients.

At best, I think the low cortisol (but not ultra-low, such as Addison's disease) findings are nonspecific and associated with chronic disease and lower activity levels in general.
 

ukxmrv

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Snow Leopard,

I had salivary cortisol levels taken when working part time and when much worse and not working at all (both with ME but at different times/years). I've also had it taken in hospital twice as a blood test. They were all low and about the same overall when compared to a range.

Low cortisol in CFS was also reported by Demitrack. There is no evidence that in patients with CFS the low cortisol is related to low activity.

It could also be argued that PWCFS have more stressful lives due to benefit cuts, money worries, family problems over the disease etc.

XMRV+
 
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Lots of things can be argued of course.
I'm pointing out that there are other explanations for the data. I'm especially skeptical of the adrenal burnout hypothesis (which is suggested as the cause for the low cortisol response) which is part of a so-called biopsychosocial model promoted by certain psychiatrists.

The fact is that there is already significant debate in the literature over the pitfalls of the various cortisol measurements. There is also significant evidence to support the idea that cortisol levels are related to activity levels (activities that cause stress presumably) and employment, at least in healthy individuals.

BTW, it is hard to draw conclusions from a study with n=1, because there can be many confounding factors. ;)
 

Dolphin

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It would be interesting if there were more scans of adrenal glands. People may recall the small study by Ted Dinan and others:

Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study.

Psychoneuroendocrinology. 1999 Oct;24(7):759-68.

Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG.

Department of Psychiatry, Trinity College Dublin Medical School, St. James's, Hospital, Ireland.

Abstract
No inclusive or satisfactory biomedical explanation for chronic fatigue syndrome (CFS) has as yet been forwarded. Recent research suggests that a dysregulated hypothalamic-pituitary-adrenal axis (HPA) may be contributory, and in particular that there may be diminished forward drive and adrenal under-stimulation. In this preliminary study we wished to examine a cohort of CFS patients in whom evidence for such hypofunctioning was found. Our aim was to establish whether these patients had altered adrenal gland size. Patients were recruited from a fatigue clinic. Those who fulfilled the Centre for Disease Control and Prevention (CDC) criteria underwent a 1 microgram adrenocorticotropin (ACTH) stimulation test, a test of adrenal gland functioning. Eight subjects (five females, three males) with a subnormal response to this test underwent a computer tomography (CT) adrenal gland assessment. Measurements were compared with those from a group of 55 healthy subjects. The right and left adrenal gland bodies were reduced by over 50% in the CFS subjects indicative of significant adrenal atrophy in a group of CFS patients with abnormal endocrine parameters. This is the first study to use imaging methods to measure adrenal gland size in CFS. It is a limitation of this study that a selected CFS sample was employed. A future larger study would optimally employ an unselected cohort of CFS patients. This study has implications not only for the elucidation of CFS pathophysiology, but also for possible therapeutic strategies.
It would be interesting to see how consistent this finding was within people. I know one person (not me) who contacted Ted Dinan - TD said he thought that the adrenals had perhaps been overactive initially and had worn out/atrophied i.e. suggesting it was more permanent.

I, of course as a patient, don't like to hear about "permanent damage" so hope changes aren't permanent.
 
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Permanent damage doesn't mean untreatable pharmacologically though. It is speculative to suggest that it is due to atrophy, it would be interesting to see the effect of length of illness on the observations - or any changes after recovery!

Note that:
The sample was a CFS subset, 8 of 52 referrals, 40 of which had a CFS diagnosis.
Each of the eight subjects had a blunted response to the low dose ACTH (1 μg) infused at 14: 00 h; blunting was defined as a failure to achieve a peak cortisol of greater than 600 nmol/l at 30 min post-infusion ( Hurel et al., 1996). The testing procedure was as previously described ( Scott et al., 1998b).
That study "The low dose ACTH test in chronic fatigue syndrome and in health" states that:
Baseline cortisol values did not differ between CFS patients and healthy subjects. The δ cortisol (maximum increment from baseline) value was significantly lower in the CFS than the volunteer group (P < 0.05). Comparison of the + 30 min cortisol values revealed no significant differences. Using an incremental cortisol of > 250 nmol/l as an arbitrary cut-off point, two (10%) of the healthy subjects and nine (45%) of the CFS subjects failed the test on this basis (χ2 = 4.3, df = 38, P < 0.05).
Those two healthy subjects were both men.
Marginally higher baseline cortisol levels in the CFS compared to the healthy subject may account for the blunted cortisol response seen. This difference in basal values was non-significant, undermining this as a likely explanation. It would nonetheless be interesting to repeat this study in CFS subjects pre-treated with dexamethasone. That an inverse relationship was established in the CFS subjects implies that the lower the basal cortisol value, the greater the incremental cortisol release. A possible explanation for this is a supersensitivity of the adrenocortical receptors to circulating ACTH, secondary to a mild ACTH deficiency and understimulation of the adrenal glands. Imaging studies of adrenal gland volume would further this hypothesis.
There is also the usual discussion that sampling times, intervals affect results.

Imaging studies require normalization procedures and I'm not sure what they were, since I don't have access to the Vincent 1994 Normal gland size study.

The study also states
No subject in this study had a concurrent DSM III-R major depressive disorder. In major depression, as demonstrated in both CT (Amsterdam et al., 1987) and MRI ( Rubin et al., 1995) studies, the adrenal glands are hyperplastic, with enlargement during a depressive episode of up to 70%. These findings are consistent with the currently held theory of HPA over-activity, related to CRH hyperdrive, as central to the pathogenesis of depressive illness ( Nemeroff, 1996). This is manifested biochemically in elevated basal cortisol levels ( Gibbons and McHugh, 1963) and raised 24 h UFC profiles ( Carroll et al., 1976). These findings are the diametrical opposite of CFS abnormalities, rendering it unlikely that CFS is simply a variant of an affective disorder, as has been previously suggested.
So enlargement during anxiety and stress and shrinkage during ????.

But then we also have:
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2265.1999.00856.x/full
(no response to low dose ACTH)

BTW, A local group here is planning on doing a longitudinal MRI imaging study on women with post-EBV fatigue. I think they also have an article in JMRI coming out in January?
 

ukxmrv

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Snow leopard,

I'm also sceptical about the adrenal burnout theory around CFS and cortisol levels. There is no evidence that PWCFS have high cortisol before their illness or at any time in it. The only patients with high cortisol (as per depression) are Simon Wessely's and Demitrack commented at the time how different this was.
 

WillowJ

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I'm skeptical of the cortisol-causative and adrenal-burnout theories, too, except as possibly subsets.
 

WillowJ

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I wasn't pleased to see that reference either [or reference 11 which is actually the same data set (Wichita 2-day study) which was analysed by different groups]. But at least this study investigated the issue - it didn't really depend on that reference (like a literature review might).

I stopped studying biology aged 16. I find it useful when researchers give just enough information that somebody without higher training might be able to understand a paper or at least the rationale. I find I can get the jist of lots of papers without fully understanding the biological systems involved.

I have come across the concept of apotosis a few times over the years. But don't mind a little reminder about what it is (which can remind me of a something a little more detailed I read).
right on the first count

on the secont point, I'm glad it was useful. I imagine they know a lay audience is reading these papers. :)
 

Dolphin

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on the secont point, I'm glad it was useful. I imagine they know a lay audience is reading these papers. :)
Another example might be mitosis vs meiosis - if they put in a few little reminders now and again, it can be useful. It probably helped that in this case a lot of the authors aren't biologists.
 

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My guess is that cortisol is a secondary player that does, nonetheless, effect immune functioning. I don't know how mildly low cortisol levels can produce a horrendous effect....If the receptors aren't working well - perhaps its possible....but it seems like a stretch..