PHOENIX RISING

During his three-hour presentation, Dr. Cheney will discuss his latest research and treatment findings. These include (but are not limited to: Diastolic Dysfunction in CFS / Patent Foramen Ovales in CFS / Therapeutic Responses to Cellular Energy Therapy/Echocardiography / Oxygen therapy in CFS. This time a 2-DVD set will come out of this appearance.

 Or you can join at the group's home page: http://health.groups.yahoo.com/group/CFS_politics

A – several difference making papers on CFS pathophysiology

B – a difference making paper on CFS pathophysiology plus several important ones

C - several important papers on CFS pathophysiology

Are people born with a predisposition to CFS? How much of a role heredity plays in who gets CFS has puzzled researchers since its onset. Dr. Cheney reportedly thought it played a mild to moderate role. Several familial studies, however, found evidence that CFS tended to ‘run in families’. These methods these studies employed, however, have been criticized.

A familial tendency towards CFS is also not synonymous with a genetic tendency towards it. This is because families share not only genes but a similar environment as well. Since it only takes one person to serve as a vector for a pathogen it is possible, for instance, for members of a family to face increased exposures to particular pathogen relative to the community around it.

Twin studies can also help disentangle the effects of heredity and environment. Five twin studies have indicated from low (25%) to moderate (43-51%) effects of heredity. The largest twin study, done in 2005 (click here) found that heredity played a modest role in CFS. Just as in the other studies, however, there are methodological limitations to twin studies.

Another way to look at the heredity question is to assess if the genes in CFS are subtly different from those in the general population. Thus far five studies have examined an array of endocrine, neurological and immune genes to see if the genes in CFS patients are different. These are the focus of this edition of Phoenix Rising

Fortuitously, several immune and neuroendocrine gene mutation studies appeared at the same time. First we take a look at immune gene mutations.

This study examined mutations in genes coding for the immune messengers called cytokines. Unfortunately I could only get the abstract of this paper.

On the other hand, increased levels of T cell activation suggest a pro inflammatory state is present in CFS. Pro-inflammatory cytokines have recently been associated with fatigue and/or other fatiguing diseases such as multiple sclerosis and cholestatic liver diseases. They are also largely believed responsible for producing the symptoms one has when sick. Some studies have suggested tumor necrosis factor alpha (TNF-a) plays a role in CFS. The high levels of oxidative stress present in CFS could be the result of high pro-inflammatory cytokine activity.

Thus there is evidence for the existence of a pro or anti-inflammatory state in CFS. De Meirleir has stated that the immune system in CFS is both under and over activated. This paper does not resolve this issue but it is the first study - surprisingly given a long history of immune research in CFS - to assess whether or not CFS patients have a genetic predisposition towards pro-or anti-inflammatory cytokine activity.

Two studies using a more accurate test involving TNF-a production in response to an immune stimulant (lipopolysaccarides, endotoxins), found either normal or reduced TNF-a production in CFS while one early study (1991) found increased TNF-a production. While TNF-a levels were not increased in CFS relative to controls in a recent study, the response CFS patients had to TNF-a was. Thus instead of having higher levels of TNF-a, CFS patients appeared to display an exaggerated responses to it. (What a twist that is! A similar situation occurs when rats with cholestatic liver disease respond to negligible amounts of the IL-1B cytokine with severe fatigue.) Gaab posited that high levels of stress over time lead to a supersensitization to TNF-a and other cytokines in CFS. This suggests that even moderate amounts of TNF-a could be too much for CFS patients.

Increased TNF-a levels could effect many problems seen in CFS including increased oxidative stress, chronic immune activation (‘sickness behavior’), metabolism (obesity) and nervous system problems (fatigue, etc.)

This study takes a detailed look at how commonly mutations occur in the gene encoding the receptor for cortisol in CFS.

With fifteen studies to date and counting (one was released just last month) cortisol has been far and away the most well studied subject in CFS. This is the first full-court press the CDC has done on the mutations in a gene in CFS. Why have the CDC and others been so interested in cortisol?

A closer examination indicated that five of the nine polymorphisms were significantly increased in CFS and that people homozygous for four of them were two or three times more likely to have either CFS or IF. Everyone carries two forms of a gene. Being homozygous for a gene means carrying the same two forms. One mutation in particular (A - rs1866388) was associated with increased fatigue, symptom severity and disability.

CFS patients also displayed increased rates of linkage disequilibrium in one section of the NR3C1 gene. A correlation analysis indicated that the patients with the most fatigue had the highest rates of linkage disequilibrium (LD).

The increased mutation rates in the gene coding for the cortisol receptor suggest that its function is altered in significant numbers of CFS patients. If this is so then the effects of the low cortisol levels seen in some CFS patients may be exacerbated by a reduced ability of their cells to respond to cortisol, i.e. these CFS patients may have difficulty utilizing the already low levels of cortisol available to them.

This was the most extensive exploration yet undertaken into the structure of a single gene in CFS and it was highly successful. Given the results – increased mutation rates in CFS patients, a positive association between gene mutation levels and symptom severity, the high levels of linkage disequilibrium present and their correlations with fatigue, and the identification of one particularly prominent polymorphism – it was not surprising that the CDC believes more analysis of this gene is called for. The authors proposed that a ‘fine mapping effort’ in the region of the gene where the linkage disequilibrium was found should be done.

Of all the Pharmacogenomics papers this one made the biggest splash in the press. It was this study that suggested CFS patients have a genetic predisposition to their disease centered in a group of mutations (single nucleotide polymorphisms (SNP’s)) occurring in a set of neuroendocrine genes. Most studies attempting to determine if a mutation in a genes increases one’s risk for a disease contrast how frequently that mutation occurs in patients versus controls. This study, like most others in these reports, took a systems approach. Instead of looking at whether one or a handful of polymorphisms were more commonly found in CFS patients, these researchers looked at a suite of about 50 inter-related neuroendocrine genes containing about 500 polymorphisms.

• Serotonin – A vasoconstrictor and neurotransmitter, liberated by blood platelets, that inhibits gastric secretions and stimulates smooth muscle; present in relatively high concentrations in two areas of the central nervous system (basal ganglia, hypothalamus) that are of special interest in CFS (See Central Fatigue in CFS). Smooth muscles are found in the internal organs including the lungs and lining the blood vessels. The vast majority of serotonin is not found in the brain but in the plasma, gastrointestinal tract and immune tissues.
• An endocrinologist, Dr. Cleare, has posited that that reduced serotonin receptor activity (possibly in response to high serotonin levels) could cause a wide variety of involving sleep, pain, motivation and sexual activity among others in CFS and other diseases (click here). Reduced serotonin activity has been found in both depression and anxiety.
• A recent study finding of decreased gastric emptying in CFS suggests that low serotonin levels could also contribute to the gastrointestinal problems found in CFS. Both Dr. Cheney and Dr. De Meirleir believe that gut problems can contribute significantly to CFS. Several studies also suggest that low serotonin may contribute to the pain in FMS. Serotonin also plays a role in the distribution of on body fat – an intriguing finding given the increased waist/hip ratio’s found in CFS.
• The 2003 Narita study found increased rates of a mutation in the in a serotonin transporter gene that results in increased serotonin uptake. By reducing serotonin levels in the synapses of the nerves this mutation could also lead to reduced serotonin activity in CFS. A recent study also suggested that reduced serotonin activity contributes to the pain in FMS. It is conceivable that altered serotonin activity in different parts of the brain contributes to the fatigue and pain in CFS and FMS respectively.

• Norepinephrine (NE) – a sympathetic nervous system (SNS) agent (catecholamine) produced in response to low blood pressure and physical stress, NE regulates blood flows (constricts blood vessels) and is an immune system regulator. Reduced NE levels could result in increased inflammation via increased TNF-a, IFN-y, nitric oxide production etc. Increased NE, on the other hand, could lead to reduced blood flows and predominantly anti-inflammatory cytokine production.
• Epinephrine (E) (adrenaline) – another SNS catecholamine, epinephrine causes increased heart rate and force of contraction, vasoconstriction or vasodilation, relaxation of the bronchiolar and intestinal smooth muscles, glycogenolysis, lipolysis, and other metabolic effects. Epinephrine also helps regulate (inhibit) the immune response.

• Corticotropin releasing hormone (factor) – sits at the top of the HPA axis. It stimulates the pituitary to produce ACTH which in turn prompts the adrenal glands to produce cortisol. A main initiator of the stress response, low CRH production could result in low cortisol levels.
• Cortisol – the main adrenal stress hormone increases blood glucose levels (energy), moderates immune activity and regulates HPA axis activity during stress.

This study appears to provide powerful evidence that CFS patients have inherited gene mutations that impair their responses to stressors such as exercise, infection, etc. How important these mutations are, however, is unclear. This study got the most attention in the press but was it the most significant? It was not a slam dunk. The authors stated that the accuracies – 75% accuracy in differentiating CFS patients from controls - did ‘not look spectacular’ and noted that researchers really like to see a 90%+ classification success rate. Some outside researchers have questioned the validity of the results given the relatively low number of samples. Others questioned whether other sets of polymorphisms might have produced better results. The authors noted that their accuracy would have been improved not by winnowing out some of the CFS patients but by eliminating those healthy controls who now or earlier had suffered from a bout of long-term unexplained fatigue. Surprisingly this turned out to apply to about 15% of the healthy controls and suggests these factors do play a role in the production of fatigue.

Despite the low accuracy levels displayed, the authors appeared to be quite enthusiastic about their results, saying

"What is encouraging is that this rather mysterious and elusive illness called CFS appears to be finally yielding to attempts at biomarker discovery."

This study is being enlarged and replicated in a different group of CFS patients. We didn’t have to wait long for a validation of its results. Just a month or so after the Pharmacogenomics studies were published we got word that another large research effort involving the same data base had been completed. In June the CAMDA (Critical Assessment of Microarray Data Analysis) conference met to report their results.

• _ Glucocorticoid receptor (cortisol) NR3C1 - 8
• _ Tryptophan hydroxylase (TH) – 5
• _ Corticotropin Releasing Hornone Receptor 2 (CRHR2) – 4
• _ Catcehol-O-Methyltransferse (COMT) – 4
• _ Monoamine Oxidase B (MAOB) – 4
• _ Propiomelanocortin (POMC) – 4
• _ Corticotropin Releasing Hormone Receptor 1 (CRHR1) – 2
• _ Corticotropin Releasing Hormone (CRH) – 2

Given the fairly large data set (50 genes) the congruence of the results is remarkable and suggests that alterations in genes involved in hormonal (cortisol, corticotorpin releasing hormone) and neurotransmitter functioning (serotonin, norepinephrine/epinephrine, dopamine) interact in ways that predispose one to CFS.

I do know that I received antibiotic treatment as a baby for ear infections, and as a five-year old I received a vaccination when I moved into a just painted naval Quonset hut after having stayed with an abusive family for several weeks while my father was in the hospital.  I began experiencing IBS symptoms the next year, and then when I was eight I began having bouts of pharyngitis and flu-like symptoms. 

For five years in my teens I was put on various antibiotics for acne, and I dropped that treatment when I learned that antibiotics could cause stomach upset.  The military doctors that I had been seeing had diagnosed me with a "nervous" stomach--totally ignoring the antibiotics I was on.  Throughout this time my energy would go up and down.  At 18 I went to an allergist and learned that I had a boat load of allergies; we--my family and I--attributed my bouts of flagging energy to the allergies.

When I left home at 20 my general health improved--that is, I had fewer episodes of flu-like symptoms.  At 22, I was hit with an intense bout of fibromyalgia (of course there was no name for it back then and I waited the symptoms out, never seeing a doctor).  I think I had had fibro symptoms before, but at 21 a car I was traveling in hit a tree at 65 mph and I think that was that.

By my early to mid 20s I got tired of doctors who had no answers as to why I kept getting the flu-like symptoms and also looked at me as if they wished I would just go away, and so I did--I quit going to doctors for about 8 years.  By that time, I knew I had weird reactions to perfumes and household chemicals.  I couldn't tolerate air fresheners.  I was also experiencing odd symptoms all the time.  My hands had not stopped hurting since the bad bout of fibro at 22; I'd had problematic low blood pressure since my teens, continual headaches since childhood, bouts of dizziness, non-stop ringing in my ears starting at 22, etc. 

I finally figured out that I was extremely sensitive to cigarette smoke (my health improved when I left home because I was no longer living with smokers), cats, and paint fumes, and also that each of these could trigger the exact same flu-like episodes and pharyngitis.  I came to see these episodes as full-body immune responses, but my doctors simply looked at me.

For a number of years, I managed to avoid cats, paint, and cigarette smoke (quite a feat in the age before it was banned in most work places), and I found that I never had a sick day off from work.  I felt bad all the time, but I did not experience the flu-like symptoms.  Then, in my early 30's I had an accidental exposure to paint and was sick for three weeks.  The allergist I consulted was "intrigued" by the oatmeal like matter that I would cough up from my lungs when exposed to paint, but his interest resulted in not so much as a "stay away from chemicals" because of his fear that he not plant the idea in my head that I might have chemical sensitivities.  Around this time, I noticed that the bouts of flagging energy I'd been having was increasing--that is, I was having more of them. 

Then, at the beginning of my second year of law school, I began experiencing explosive diarrhea after allowing my apartment to be sprayed for roaches several times in a couple of months.  (Because I have minimal reactions to most other chemicals--other than Lysol, ammonia, moth balls, air fresheners, bleach, paint, polyurethane--, I thought I could handle pesticides.)  This ongoing dis-ease led to some surgery and a terrible IBS diet, which I had to boot along with the doctor who suggested it (the same doctor who looked at me like I was crazy when I said that I thought the pesticides had caused the problem). 

I did the allergy diet and discovered that my body was rejecting--of all things--foods that were not low in carbohydrates.  So I researched all I could about nutrition and supplements, cut out sugar, made my own bread and mayonaise, went on a very low carb diet, gave up dairy and red meat, ate 75% raw foods, and took handfuls of supplements several times a day.  After about six months, the diarrhea stopped and one bright and glorious day my energy returned.  (One way the body can rid itself of pesticides is through rapid weight loss; it seemed my body knew this and rejected carbohydrates.  A very low carbo diet will result in rapid weight loss, but don't try this at home without a doctor's supervision because it can kill you.  I did this on my own because I could not find a sympathetic doctor and I was willing to risk death to find health.)

And then at 39 (after being run over by a car as a pedestrian, my dog dying, leaving my husband, moving, my brother being diagnosed with AIDS, and my being laid off), my health began to deteriorate again, and--duh!--I thought that the diet and nuitritional supplements weren't working.  Actually, I noticed a severe dip in my energy when I started working full-time again after taking a year off after law school (and the car accident).  (Funny, as physically exhausting and difficult as law school is, I found it less stressful than WORK even though I put in more hours in school.) 

...and so I gave up the diet and the supplements (I thought it was just something else that worked for a while and then failed...like antihistamines).  And my energy went up and down and up and down.

When the (mono?) fatigue finally left (that is, when it finally lessened) after 4 1/2 months (I worked the whole time, although I would cry when no one was around because I was so fatigued), I realized that I had to stop pushing myself.  I had to save all of my energy for employment (for that all important paycheck), and so I gave up all volunteer work.  By now, I'd become incredibly good at "faking it."  As far as I was concerned I was going to fake myself into an early grave, and an early grave was preferrable to figuring out how I was going to support myself without an income.  (Or live a dull and unfulfilling life.)

Within two years of that probable bout of mono I was going down and not coming back up.  I asked my employer to let me work from home, and finally months later when I asked to work 3/4 time from home for 3/4 pay, my employer let me work full time at home.  But it was too late.  That winter I had the second non-mono virus as an adult.  And by spring I was in full denial mode.  I had a mortgage, law school loans, and I couldn't see how I would survive without a paycheck. 

Not long after I turned 48--just two years after I started working from home--, I mentioned to a co-worker that I thought I had mono again.  This was at the beginning of a five-day, 67 work week, where I was on my feet most of the time managing a conference (although I was working from home, I was still responsible for four week-long conferences each year).  I proceeded to have these viral symptoms on and off for six weeks when my partner begged me to see my doctor.  (By the end of the six weeks I was lying across my keyboard with only enough energy to answer my email.) Although my doctor was skeptical--"most people do not have mono more than once"--, he tested me and found that I had a new mono virus. 

And so, I finally allowed myself to crash, and I have been disabled ever since.  I never thought then that I would still be so sick now.  (I was confident I'd recover in a couple of months--such denial!)  I never thought that I'd continue to lack brain power.  Although it should have been obvious to me that I have been on a downward spiral all these years (that even my ups had become less up over time)--obvious to me had I not had a long-term affair with denial--, I had always managed to work, to support myself.

Finally, after years of denial, I accept the fact that I have an illness that is made worse by stress, and I think that diet and supplements do help.  As I look to the future, I look forward to learning how to enjoy life more and stress less.  And if I recover a semblance of normal energy, it seems clear to me that full-time work combined with the errands required for every day life is more than my body can take. 

Obviously, this is not the life I wanted or worked for.  I have multiple talents just not the ability.  The spirit is willing but the body is not able.  I suspect this is true for many people who are ill. 

eclairepride-comments@yahoo.com.