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Chronic Fatigue Syndrome

This is a work in progress and is being updated regularly. Check back regularly, as I will be steadily improving the site and adding more information.

Chronic Fatigue Syndrome / ME / Post-Viral Fatigue Syndrome / CFIDS / CEBV

The illness is also known as chronic fatigue immune dysfunction syndrome (CFIDS), and outside of the USA is usually known as myalgic encephalomyelitis (ME). In the past the syndrome has been known as Chronic Epstein-Barr virus (CEBV). Chronic Fatigue Syndrome is also mistaken for Fibromyalgia which is a chronic musculoskeletal syndrome.

In CFS/ME it seems that we should see this as an illness probably caused by enteroviruses, acting on a body that is for many reasons already stressed biologically, with high pre-morbid levels of oxidative stress, resulting in high peroxynitrite levels. Other biological stressors may be the cause or add to this, such as IAG or these may be mechanical, dietary, environmental, physical, infective or psychological.

What seems important is that the blood-brain barrier becomes permeable allowing viral entry. Treatments should be aimed at identifying and removing these stressors

There also exists a chronically activated immune system, which may result from the initial insult or co-existent microbial, or toxin overload or a combination of the two. It seems that there is over-expression of aberrant RNA, derived initially from an enterovirus, protected by a viral type coat which in the presence of LMWRNase L leads to extreme ATP depletion... Pollution and vaccines have been suggested as a cause for the loss of control of HERV associated mRNA production. Following this hypercoagulability develops, causing problems in both blood and lymph microcirculation's. This hypercoagulability may arise from a combination of hereditary, immune mediated and oxidative stress pathways. We have chronic sympathetic system activation, from many causes.

Multiple subtle endocrine changes are also present in the CFSME/FM complex, both quantitatively in terms of hormone levels, and also qualitatively, with loss of circadian rhythmicity. Given the bi-directional flow of information between the nervous, endocrine and immune systems, we are presented with a perfect example of Chaos Biology. This results in a failure of homeostasis and homeodynamics. Simply stated, a body that cannot respond to any form of biological stress, be it environmental, infective, physical or psychological.

Medical history is littered with illnesses that were thought to be psychogenic e.g. Tuberculosis, epilepsy and Hypothyroidism.

Chronic Fatigue Syndrome/ME and Fibromyalgia plus Associated Syndromes
Evidence for their organic basis: A summary of the suggested underlying pathophysiologies and treatment approaches
Dr. Andrew John Wright


The epidemiology data below is mainly from the pen of Dr. Betty Dowsett, Hon. Consultant Virologist.

"The illness usually affects young to middle aged adults.  The studies which have been done tend to show that this is mainly a disease of temperate climates, where bowel and respiratory infections are seasonably interrupted. This is in comparison with tropical areas, where solid adult immunity exists, by the reasons of continuous exposure to infection and where lesser standards of hygiene persist.

"Of the studies that have been done, the average statistical increase in the incidence of ME between l965 and l990 was between 50 and 70%.  It is thought that this is possibly due to an enteroviral infection.  The majority of patients, between 60% and 80%, report that a 'flu'-like illness rushes in the onset of ME, which is more common in Summer and Autumn than in Winter and Spring (63% compared with 37% in a study of 225 patients).

"Studies show that the commonest age of onset in both sexes actually lies between the third and fourth decade. There is unity of ratio between males and females until puberty and then a 3 to 1 ratio develops between females and males. 

"In an analysis of 420 patients who presented between ten days and two years of the onset of the illness, 31% were seen to be improving; 20% were still fluctuating between relapse and remission; 25% had achieved a steady level of disability, and 24% had experienced no remission or were deteriorating.  This shows CFS/ME is not a short-term illness and improvement does not proceed in a linear fashion.

"If it is an enterovirus that initially commonly circulates in local populations, the effects are probably asymptomatic in the majority.  However, those people affected through genetic and environmental factors then go on to develop disabling fatigue.  This is probably around 6% of those exposed.  However, although around 25% to 30% improve, the others develop a more serious multi-system disease involving cardiac, endocrine and immune system abnormalities.  Unfortunately, there appears to be a lifetime risk of relapse in all patients."

  Number Spring Summer Autumn Winter
Acute Onset 184 23.4% 18% 29% 29%
Chronic Decline 86 29% 18.6% 28% 24.4%

Therefore there seems to be a lull in summer.

A recent population based study in Chicago, using telephone screening and medical screening for those identified with Chronic Fatigue Syndromes, revealed an incidence of 422/100,000. The highest incidence being in women aged 40-49, amongst ethnic minorities and those with poor education and socio-economic status.

A further study sponsored by AfME and the SAMEC Trust also showed a high incidence in ethnic minorities, but also little understanding amongst the population, as it has always been viewed as an illness of white middle classes. This leads to a reduced quality of life, inability to work, and depression.

In Short: 60-80% report a flu-like illness begins CFS. The commonest time of onset is age 20-30. CFS is not a short-term illness and fluctuates between periods of being more or less debilitating. There appears to be a lull in symptoms in summer.


CFS Symptoms

Chronic fatigue syndrome (CFS) is an emerging illness characterized by debilitating fatigue (experienced as exhaustion and extremely poor stamina), neurological problems, and a variety of flu-like symptoms.

The core symptoms include excessive fatigue, general pain, mental fogginess, and often gastro-intestinal problems. Many other symptoms will also be present, however they will typically be different among different patients. These include: fatigue following stressful activities; headaches; sore throat; sleep disorder; abnormal temperature; and others.

The degree of severity can differ widely among patients, and will also vary over time for the same patient. Severity can vary between getting unusually fatigued following stressful events, to being totally bedridden and completely disabled. The symptoms will tend to wax and wane over time. This variation, in addition to the fact that the cause of the disease is not yet known, makes this illness difficult to diagnose.

For a slight majority of patients, the illness begins suddenly as though one had come down with the flu. Except that this "flu" doesn't seem to completely go away. For many other patients, the onset appears gradually over a long period of time.

In many cases, a high-stress event seems to "trigger" the illness. There are many cases in which CFS appears to have begun with a severe head injury, for example. But since such events seem to have no apparent logical connection to the illness that follows, many have speculated that the CFS was latent in people beforehand in these cases, and that the stress of trauma merely triggered the stress-hypersensitivity aspect of the illness. Some have further speculated that other stressful factors in our environment, be they microbes or pollution, may also prompt this illness to bloom.

The illness varies greatly in its duration. A few recover after a year or two. More often, those who recover are more likely to do so from 3 to 6 years after onset. Others may recover after a decade or more. Yet for some, the illness seems to simply persist.

CFS often occurs in cycles. It can be frustrating to obtain some relief, but then not know whether you have recovered or if you are merely between cycles.


Notice that this is an almost exact description of the symptoms of Gilbert's Syndrome, even as far as the cycles of symptoms and the triggers that set it off. Such a high degree of similarity implies a close correspondence between GS and CFS.

Chronic Fatigue Syndrome/ME and Fibromyalgia plus Associated Syndromes
Evidence for their organic basis: A summary of the suggested underlying pathophysiologies and treatment approaches
Dr. Andrew John Wright

In a study of 66 CFS/ME patients and 53 healthy controls blood was analysed using reverse transcriptase PCR using primers for nontranslated enteroviral sequences. The blood was analysed for the presence of a prominent 750base pair sequence previously reported in 12 out of 24 Gulf War Veterans. 77% of patients had a prominent 750 base pair sequence compared to 0% of the controls.

Interestingly Dr Brooks has shown a specific deficit using this technique. CFS/ME patients have significantly reduced levels of N-acetyl aspartate in the right hippocampus signifying neuronal death. Similar changes have been found in the brain stems of Gulf War Veterans. Poor blood flow to the thalamus has also been reported.

These findings help explain problems with cognitive functioning and central processing of information.

Although I accept that my observations are open observations, the main abnormalities I  found were:

Abnormal melatonin rhythms

These were sometimes high outputs of melatonin and these were often phase shifted by 6 to 12 hours, giving the sufferer a syndrome, I suppose, similar to severe jet lag. In a review of my first sixty patients, this occurred in 36% of cases. Interestingly there was no melatonin output in 60% of cases, patients therefor losing the main molecular manifestation of darkness. As sleep is in part induced by melatonin triggered elevation of Prostaglandin D2 in the Histamine-Interleukin–Prostaglandin pathway, these problems may explain patient's problems with sleep initiation. This possibly indicates problems with enzymatic conversion of serotonin into melatonin, or internal desynchronisation between the suprachiasmatic nuclei in the hypothalamus

Abnormalities in cortisol and DHEA

These hormones form a major part of the catabolic / anabolic balance in the body. Cholesterol is converted into pregnenolone by the adrenals. It then goes one way to produce the 'Structural' hormone DHEA from which Oestrogen and Testosterone are made, and the other way to the 'Functional' hormones cortisol and progesterone. As an analogy, when considering their effect on cell structure and organisation, the structural hormones are like house builders and the functional hormones are like interior decorators. Invariably, DHEA levels were low, a point discovered by other workers, but cortisol levels fluctuated. They could be high or low. They could also, over a period of a day, be normal in level, but were not produced rhythmically. Indeed, they often showed flat output curves, which are biologically useless. The body relies on steroid hormones to change concentration in order to be read as a signal, rather like listening to FM radio. It is the velocity of change that is important as well as permissive levels. Levels also changed over time in the same patients, but invariably, the sicker patients had a low output of cortisol and DHEA. Most patients show a catabolic dominance. Recent urinary amino and organic acid studies have shown an increase in protein breakdown, which may result because of an altered Cortisol and DHEA ratio, or Growth hormone / IGF-1 abnormalities.

One of the larger studies that has been carried out is that by Dr. Lucinda Scott for her PhD thesis, 'The role of the HPA axis in Chronic Fatigue Syndrome.' Her main findings were:

a) Low levels of DHEA and cortisol

It would seem that in CFS/ME, there is a specific problem with the CRH receptor, with it being down-regulated, or the V1b receptor, which is the one that Vasopressin acts on, being upregulated. In humans, Vasopressin is not as effective an ACTH releasing agent. Therefore, in CFS/ME, where people are unable to use this as their main hypothalamic pituitary stress-releasing hormone, homeostasis cannot be maintained in the presence of any form of biological stress.

Another explanation would be that constant biological stress causes adrenal fatigue, i.e. constant output causes depletion of the functional reserve of the gland.

c) Central opioid tone

She then went on to look at central opioid tone in Chronic Fatigue Syndrome and found that using Naloxone to induce ACTH and cortisol release produced a blunted response. This would suggest depressed central opioid tone in chronic fatigue syndrome, which may account for some of the pain that these people experience.

d) Adrenal gland imaging

Finally, she looked at CT and MRI imaging studies of the adrenal gland and found consistently atrophied adrenals in CFS/ME. She performed this study with 8 patients who showed a poor response to the 1 mcg. Synacthen Test. A 50% reduction in adrenal size was seen. Therefore, the principal findings of her study were:

1. There is a reduction in adrenal gland size and secretory reserve.
2. End organ hypofunctioning occurs which is probably due to a deficiency of ACTH.
3. Under activity of this is not explained by increased opioid tone.
4. An increased contribution of Vasopressin to adrenal regulation is probable.

Finally, before finishing with the adrenals, it is also postulated that another steroid, 'ouabain-like' steroid, (OLS), is low in CFS/ME. OLS has mainly been researched with regards to hypertension.  It is produced, along with aldosterone, by the zona glomerulosa of the adrenal cortex.  It may be that the atrophy of the gland also causes reduction in OLS levels. It plays an important role in modulating the Na-K-ATPase pump in cell membranes. This is vital for maintaining the electrical homeostasis of the cell membrane. Failure of this regulatory enzyme has profound effects on cell energetics and may in part also account for many of the symptoms found in this illness.

CFS can also begin following after exposure to toxins including Organophosphates and chlorines, which are known to produce abnormal sodium ion channels. Finally, CFS/ME patients have increased resting energy expenditure, a state influenced by abnormal transmembrane ion transport.

It may be that down regulation of the adrenals is an attempt by the body to downregulate a system that is constantly receiving stress messages from the brain, because of sympathetic overdrive. The body can take no more and it puts you flat on your back to enforce rest. Alternatively it could be seen as part of a general downregulation secondary to hypothalamic dysfunction.

One of the other problems is the effect of the illness on thyroid functioning. It has long been noted that people are often functionally hypothyroid. That is, they produce enough thyroid hormones from the thyroid gland, as measured by levels in the blood, but they appear to be hypothyroid at a cellular level. This tends to occur in adult Fibromyalgia patients. Numerous effects could explain this:

1. The blood test for thyroid function is not a dynamic test, unlike, e.g. HbA1c. It simply represents what is in the blood, and not what is active at a cellular level. It is based on population sampling and would therefore include people with subclinical hypothyroidism. We will have to wait until the development of the nuclear membrane thyroid receptor volume test before we have a dynamic test of thyroid function. In medicine we tend to treat extremes and not subtle alterations in physiology. This means that people at the lower end of ‘normal’ are not treated. They may actually need to be at the upper end of normal, but the test will not tell you that. The body also has the ability, it seems, to keep the blood levels normal despite cellular thyroid problems. This can happen in any chronic illness.

2. In cytokine mediated illness the production of central and locally generated cytokines can affect the de-iodination pathways of thyroid hormones. It seems that high level of rT3, and low levels of T2 may ensue. Reverse T3 is a non-competitive inhibitor of T3 and is raised in stress situations. T2 is thought to be important for the functioning of mitochondria. High levels of rT3 have been found in post-operative patients subsequent to high cortisol output. It is thought to be an adaptive response in order to conserve energy. The situation of poor conversion of serum T4 to cellular T3, for whatever reason, has been called Wilson's Thyroid Syndrome.

3. Other hormones affect thyroid functioning. Cortisol is permissive for hormone uptake into cells and low cortisol levels can therefore have an effect on this.  High cortisol can also inhibit functioning through its action on rT3 as mentioned above.

4. There is hypothalamic downregulation of the thyroid axis with altered sensitivity to TRH and TSH at their receptors

The treatment studies by Teitelbaum and Ali that I quote later both incorporated low dose thyroid hormone replacement in selected patients. This seems to be of great benefit especially to fibromyalgia patients, particularly borderline hypothyroid patients (T4 in lower 1/3 of reference interval TSH >3) or those with evidence of low T3.

In Short: A genetic sequence was found in 77% of CFS sufferers and 0% of controls, which helps explain cognitive problems. Phase-shifted high metatonin output in 36% of cases and no melatonin output in the rest indicates disturbance in conversion of serotonin into melatonin and help explains insomnia. Low DHEA and oddly fluctuating cortisol lead to catabolic dominance. There is also a depressed central opioid tone which accounts for some of the pain. Atrophied adrenal glands were consistently found, 50% of normal size. It is possible that adrenals are downregulated by the brain due to constant stress messages. Another steroid, OLS, is low, leading to poor cell energetics. CFS patience expend more energy when resting. CFS can be triggered by exposure to organiophosphates and chlorines. There is a functional hypothyroidism in CFS. They produce enough hormone but are hypothyroid in a cellular level. This could be a result of cytokine mediated illness or high or low levels of cortisol.

Notes: Temperature of 97.5 often.
Common complaints: fatigue, chest pain on right side, headache, sinus congestion, foggy, light headed, cold sweats, back pain, loose stools
Doctor: “On examination your general appearance was healthy. Your blood pressure was normal… In short, you had the typical appearance of patients with chronic fatigue syndrome, which is, you looked entirely normal. Subsequently, you have had symptoms of sinusitis and have taken several antibiotics for this. Sinus symptoms are fairly common in patients with chronic fatigue, and often have no demonstrable bacterial etiology.”
“As we discussed, the chronic fatigue syndrome is a mysterious illness that can devastate an individual’s life and ability to work without producing any abnormalities on physical examination or laboratory testing.”



The cause of the illness is not yet known. Current theories are looking at the possibilities of neuroendocrine dysfunction, viruses, environmental toxins, genetic predisposition, or a combination of these. For a time it was thought that Epstein-Barr Virus (EBV), the cause of mononucleosis, might cause CFS but recent research has discounted this idea. The illness seems to prompt a chronic immune reaction in the body, however it is not clear that this is in response to any actual infection -- this may only be a dysfunction of the immune system itself.

A recent concept promulgated by Prof. Mark Demitrack is that CFS is a generalized condition which may have any of several causes (in the same way that the condition called high blood pressure is not caused by any one single factor). It *is* known that stressors, physical or emotional, seems to make CFS worse.

Some current research continues to investigate possible viral causes including HHV-6, other herpes viruses, enteroviruses, and retroviruses. Additionally, co-factors (such as genetic predisposition, stress, environment, gender, age, and prior illness) appear to play an important role in the development and course of the illness.

Many medical observers have noted that CFS seems often to be "triggered" by some stressful event, but in all likelihood the condition was latent beforehand. Some people will appear to get CFS following a viral infection, or a head injury, or surgery, excessive use of antibiotics, or some other traumatic event. Yet it's unlikely that these events on their own could be a primary cause.


Chronic Fatigue Syndrome/ME and Fibromyalgia plus Associated Syndromes
Evidence for their organic basis: A summary of the suggested underlying pathophysiologies and treatment approaches
Dr. Andrew John Wright

Immunology and Toxicology

Some of the more striking abnormalities are those found in the 2-5 Synthetase/Rnase L anti-viral pathway. These are not specific to CFS/ME though, and abnormalities can occur in other viral illnesses. This pathway works as follows: viruses activate the 2-5-synthetase enzyme. This in turn converts ATP into 2-5 oligoadenylate and activates the RNase L enzyme, which degrades viral and single stranded RNA. Various Protein kinase enzymes also becomes activated and elevated, which again inhibits both viral replication and protein synthesis. It has been suggested that environmental toxins in the presence of heat shock proteins can also activate this pathway.

Dr. Robert Suhadolnik, at Temple University, showed as far back as 1989, that activity in this pathway was upregulated in patients with chronic fatigue syndromes. Crucially in 1996 it was also noted that a proportion of patients had an abnormal version of the RNase L enzyme. This low molecular weight form is 37 kDaltons, compared with the normal 80 and 47 kDalton versions. It was thought initially that all chronic fatigue patients had this abnormal form. The most recent figures I could find by Dr. K De Meirleir showed that the low molecular weight version was found in 680 out of 705 patients. The levels quantitatively vary though, and the amounts correlate with the Karnofsky Disability Index. The low molecular weight RNase L enzyme is up to six times more biologically active and resists protein degradation. Therefore when expressed, patients suffer an even greater depletion of ATP reserves and inhibition of protein synthesis. It has been suggested that mycoplasma genus cause the splitting of Rnase L.

The overwhelming fatigue with an acute viral illness is due in part to ATP depletion in order to fuel anti-viral pathways.

Interestingly studies have shown that those suffering from Fibromyalgia do not express the low molecular weight RNase L. If confirmed by larger studies this would be a major difference between the two illnesses.

This upregulated system, either expressing RNase L or low mol wt RNase L can then cause problems to varying degrees with enzymatic detoxification pathways, particularly in the liver. It can monopolise protein synthesis and deplete essential nutrients such as glutathione. Low white cell glutathione is a feature of treatment resistant patients.

Some very interesting and important work has come from Professor Vojdani, in California. In 1998 he published a paper which showed that RNase L inhibitor, the controlling enzyme in the 2-5 Synthetase / RNase L pathway, is low in CFS/ME patients. This may be the underlying problem. The reason this occurs is not yet known.

Vojdani suggests that measurements of RNase L inhibitor and Protein Kinases can be used to show a viral aetiology and monitor relapses and remissions. Measurements of Protein Kinase 1 are very important in studying the mechanism of interference with signal transduction in lymphocytes. This signal transduction system consists of eleven different isoenzymes, each having different biological actions, and distinct abnormalities can be seen in CFS/ME patients. Also important is measuring NK cell activity, which is often low.

[graph shows CFS/ME patients with 569 RNase L inhibitor levels while normal people have 2296]

Other evidence on the importance of this upregulation and expression of the abnormal enzymes has come from the use in patients of the agent Ampligen, also called poly (1)-poly (C12U). This is a synthetic, mismatched double-stranded RNA with potent anti-viral and regulatory properties. In a double blind study involving 92 patients, measures of clinical response such as cognitive functioning, exercise ability and less reliance on other medications, improved in 80% of sufferers.

Ampligen is best given early in the illness, and in those positive for low molecular weight RNase L. Not only does it have potent anti-viral properties, it is also an immune system modifier, i.e. an allosteric modifier.  It can downregulate an activated immune system, as in CFS/ME, and upregulate a depressed immune system, as in AIDS patients.  Unfortunately Ampligen is expensive, around £6-8000 per treatment. It also has to be given IV twice a week. Relapses can occur on completing treatment and repeat courses may be necessary.

Another interesting study by Vojdani, published in 1999, showed that not only could viruses elevate the above anti viral pathway, but so could environmental pollutants, particularly Methyl Tertiary Butyl Ether, (MTBE), and Benzene, components of petrol fumes.

Whilst talking about chemicals, it is interesting to note that about 20-47% of CFS /ME and Fibromyalgia sufferers complain of severe multiple chemical sensitivities. About 4-6% of the general population also has severe chemical intolerance. The levels of chemicals needed to trigger these problems would normally be considered to be non toxic, however, host factors involving sensitisation / amplification of endogenous responses seem to be to blame.

Research to date has shown that these sensitised pathways react unfavourably with exposure to volatile organic compounds and pesticides, facilitating behavioural, autonomic, endocrine and immune function dysfunction. This is seen by sensitisability of cardiovascular parameters, resting EEG alpha-wave patterns, beta-endorphin levels and impairment of divided-attention task performance. This fits in well with Professor Behan's work. It shows that people exposed chronically to low dose organophosphates, who also have CFS/ME, exhibit a neuroendocrine profile identical to acutely exposed people. An example would be farm workers with 'sheep dip flu.' Here the results of investigations looking at serotonin, acetylcholine and brain glucocorticoid steroid receptor activity were identical in OP exposed workers and those with CFS/ME.

In Short: The RNase L anti-viral enzyme is upregulated in CFS. 680 out of 705 patients had an abnormal low-weight version of the RNase L enzyme. This enzyme is 6x more biologically active. Therefore when expressed, patients suffer an even greater depletion of ATP reserves and inhibition of protein synthesis. The overwhelming fatigue with an acute viral illness is due in part to ATP depletion in order to fuel anti-viral pathways. It has been suggested that mycoplasma genus cause the splitting of Rnase L. It is also found that the RNase L inhibitor is low in patients with CFS (569 as opposed to 2296), which may be the reason for the upregulation. Environmental pollutants can also activate this antiviral pathway. This upregulated system can then cause problems to varying degrees with enzymatic detoxification pathways, particularly in the liver. It can monopolise protein synthesis and deplete essential nutrients such as glutathione. Low white cell glutathione is a feature of treatment resistant patients. 20-47% of CFS sufferers have severe multiple chemical sensitivity. These sensitized pathways respond unfavorably to exposure to volatile organic compounds and pesticides, reacting from low doses similarly to normal people reacting from high levels of exposure.

Gilbert's Syndrome

Gilbert's and chronic fatigue syndromes in men

Gilbert's syndrome, a symptomless familial hyperbilirubinaemia, has also been described as "benign" and a condition in which "some patients complain of symtoms such as... weakness but these are non-specific and may reflect a coincidental occurrence". We report 7 men with chronic fatigue syndrome and Gilbert's syndrome

These patients were from a total of 45 men referred with chronic fatigue syndrome. Therefore 16% of this population had Gilbert's syndrome, which compares with 2% in the general population. All 7 were referred to our fatigue clinic and met the Oxford criteria for chronic fatigue syndrome. The fatigue was severe, had been present for at least 6 months, and was incapacitating. They had no conditions known to produce chronic fatigue. Liver function and gamma-glutamyltransferase concentrations were normal. There was no evidence of haemolysis.

Gilbert et al originally described a clinical syndrome associated with hyperbilirubinaemia. They described psychological symptoms that included neurasthenia, the historical equivalent of chronic fatigue syndrome. They also described bleeding disorders, pruritus, urticaria, and anaemia, which imply that not all their patients had a simple unconjugated hyperbilirubinaemia and suggest other hepatic pathologies.

Foulk et al reviewed 118 patients said to have a diagnosis of constitutional hepatic dysfunction. 58 were thought to have Gilbert's syndrome. Fatigue was the most common symptom, mentioned by 38. Gastrointestinal symptoms were also common. The investigators thought that the symptoms were secondary to anxiety about being told of chronic hepatic illness. Olsson et al isolated finding of hyperbilirubinaemia, and suggested that "Gilbert's" is merely a label applied to patients whose serum bilirubin is greater than two standard deviations above the mean.

We do not think that our observations can be attributed to the patient being told that he had a chronic liver disease because few knew they had Gilbert's syndrome when referred.

We reject the modern view that Gilbert's syndrome is symptomless, and think that it is a predisposing or perpetuating factor for the chronic fatigue syndrome, especially in men. Another illness, such as an infection, may precipitate a chronic fatigue syndrome in these predisposed men.

Note: The study states that Gilbert's Syndrome occurs in 2% of the general population, and 16% of people with CFS have GS. This would be an 8x greater chance of having CFS, but many figures I've seen say that the percentage of people with GS is 5-10%. This reveals a 2x-3x greater chance of having CFS. Still significant, but I'm curious where the oft-quoted "4x more likely" comes from.

Gilbert's syndrome and chronic fatigue syndrome

Dr Cleary and Dr White (March 27, p842) describe a high prevalence of Gilbert's syndrome (16%) in men with chronic fatigue syndrome (CFS) and suggest that "Gilbert's syndrome is a predisposing or perpetuating factor for the CFS, especially in men".

Since November, 1991, we have been investigating the prevalence of CFS among patients with severe fatigue. Among more than 120 subjects referred to out fatigue clinic, we identified 41 female and 16 male subjects with fatigue persisting for at least six months and several non-specific symptoms (fever, sore throat, myalgia, arthralgia, neuropsychiatric disturbances). 6 subjects (5 female, 1 male) met Centers for Disease Control criteria for CFS diagnosis (group A); 33 (22 female, 11 male) did not fulfill the second major criterion of this definition (absence of any other conditions producing fatigue), and an alterative diagnosis was formulated (group B); and 18 (14 female, 4 male) were classified as probable CFS (two major criteria associated with six or seven minor criteria) (group C). Gilbert's syndrome was diagnosed in 6 (11%) of the 57 patients with lasting debilitating fatigue. Gilbert's syndrome was identified in a female patient with overy CFS (1 of 6, 17%), in 2 men and 1 woman of 18 (17%) with probably CFS and in 2 women in group B (6%) with relapsing polychodritis and hypothyroidism, respectively.

As Clearly and White show, 16% of our overt and probable CFS population had Gilbert's syndrome. This prevalence is much higher than the 6% in the group with fatigue associated with causes other than CFS and the 2% in the general population. However, we identified the syndrome in women and therefore we would like to modify slightly their conclusion: GIlbert's syndrome can be regarded as a predisposing or perpetuating factor for CFS in both sexes.

In Short: This expands the above to both sexes.

PERSONAL: Gilberts Web Forums

The doctor said that as there were no symptoms with GS, these were being caused by ME. We were given a leaflets about ME and told that eventually she would get better. On her next visit another doctor didn't mention ME at all. When I questioned this he said that he didn't like people being labelled with ME (or as he preferred to call it 'Chronic Fatigue Syndrome'). He said that although medical opinion was that there were no symptoms with GS, everyone he saw diagnosed with it suffered similar symptoms. He said although there was no proof they were caused by GS, it seemed likely that GS did have something to do with it.
I had a similar experience. I tried to discuss with various Doctors I have seen over the years certain aspects of GS but the moment I mention the possibility of a link with GS there seems to be a perceivable change in attitudes. The whole experience over many years was frustrating in itself.

My Doctor eventually diagnosed Fybro Myalgia but I still ended up in the ME clinic all be it after a three and a half year wait just for an appointment. They suggested reading some books regarding approaches to life which all seemed a bit of an anti climax in the context of a desire for some relief when symptoms were at their worst. When I mentioned the wait for the appointment I was just advised "it was a very busy department". Now there's a thought.
Its disturbing to see that the majority of GP's are still ignorant to ME & GS. I agree with you that ME/CFS is often wrongly diagnosed as the illness where recent evidence (for me at least) clearly points to GS.

Has anyone had ME or CFS (Chronic Fatigue Syndrome) with Gilberts? I have had CFS off and on since 1985, but Gilberts only started to show up in the past two years.
When I first got sick around 1990 the docs all assumed it was CFS because all the symptoms were there. They ran lots of tests for everything including poisoning, and then decided it may be CFS but was probably just exhaustion from overwork and yada-yada. I never really bought that idea. The Gilberts turned up in the tests (they told me as an aside but reassured me it was nothing at all) and they never put it together as the possible root cause but now that I am more informed I believe that is the case.
There is a set of symptoms that is now recognised as CFS, and I quote below:
"Chronic Fatigue Syndrome/Fibromyalgia (CFS) is an emerging illness characterized by debilitating fatigue (experienced as exhaustion and extremely poor stamina), neurological problems, and a variety of flu-like symptoms. The illness is also known as chronic fatigue immune dysfunction syndrome (CFIDS), and outside of the USA is usually known as myalgic encephalomyelitis (ME). In the past the syndrome has been known as Chronic Epstein-Barr virus (CEBV).

The core symptoms include excessive fatigue, general pain, mental fogginess, and often gastro-intestinal problems. Many other symptoms will also be present, however they will typically be different among different patients. These include: fatigue following stressful activities; headaches; sore throat; sleep disorder; abnormal temperature; and others. The degree of severity can differ widely among patients, and will also vary over time for the same patient. Severity can vary between getting unusually fatigued following stressful events, to being totally bedridden and completely disabled. The symptoms will tend to wax and wane over time. This variation, in addition to the fact that the cause of the disease is not yet known, makes this illness difficult to diagnose"
Like you, I wonder if Gilberts has not been the cause all along. You wonder how 'benign' it is, given that there are a number of us who are identifying the same health problems. For me, I regularly have a sore throat, swollen glands and fatigue, sometimes fever, and fairly frequent headaches. My acupuncturist has identified the liver as a real problem for me (before I knew about Gilberts).
I got sick in the big wave back in 1985/1986, with CFIDS. About 6 years after that fact & previous blood test results, is when my bilirubin began to exceed the high limits significantly. It has been elevated since then, and at the end of 2001 I had new blood work that showed I was even higher. I have never recovered from CFIDS and I'm having the neuro problems now for the last several years.
SNap! I was diagnosed with Post-Viral fatigue syndrome (also knowb as ME or CFS or CFIDS) nearly 10 years ago and my liver tests came up with Gilberts Syndrome, but they said it was nothing to worry about. SO, I had the diagnosis ME!
Now I am in a relapse I went to see Dr Hyams who is a harley street specialist of ME/CFS and he is giving me high doses of vit B12 (like 25000% RDA 3 times a day) and I might need some injections of Glutathione...he did say that people with Gilberts are more suceptible to getting ME/CFS.....but then noone know what ME/CFS really is after 50 years of looking and the doctors say that GS doent cause any symptoms.
I was diagnosed with GS in 1990. That diagnosis also coincided with a diagnosis of meningitis, twice in one year, and also glandular fever, from which it's suspected that I had/still have CFS. The CFS diagnosis was arrived at by doing a Live Blood Test (in Australia), which means the practitioner can actually see white blood cells as they "swim around" in your blood sample and count them, and also identify which type they are. This gives a clear picture in conjunction with blood tests as to a diagnosis.

What was found in my case was that there were many "left over" white cells used in killing Glandular Fever, and that these should have by that time disappeared from the blood stream unless the body had not fully recovered (and now I know that is often the case with takes us longer to get over viruses) and therefore, along with all my symptoms I still had (and have), a diagnosis of CFS was made.

It is now 2002, and I'm still battling this, only now I have alot more information thanks to everyone's feedback here......K.
Wow! What an interesting thread! I have a diagnosis of post viral fatigue syndrome (CFS/ME). I just came across this website yesterday when I was doing a bit of research into my CFS. I have slightly elevated bilirubin levels and wondered what this has to do with the CFS. Well that was how I learnt about GS. I must stress that I have NOT been diagnosed with GS but I'm just beginning to wonder if it might be a possibility

PERSONAL: Gilberts Web Forums

At one point my 15 year old daughter was told by one doctor she had Chronic Fatigue Syndrome as well as GS. We think this was the doctors way of saying GS is benign so we need an answer for the symptoms! WE don't think she has CFS at all.

Note: Carl also has GS.

Is Glutathione Depletion an Important Part of the Pathogenesis of Chronic Fatigue Syndrome?
It talks about Gluthathione Depletion with respect to Chronic fatigue. I have absoltuely no medical knowledge but I can see plainly the thread of Gilberts/Gluthathione/phase 2 pathway/endocrine/hormone/fatigue/psychological/etc. It has become obvious. I would like to hear your comments on the site in general. CFS research - there is some very interesting stuff- the links are all there and they just need linking to GS.

This is another forum that discusses glutathione a lot in the context of chronic fatigue.

I was supposedly diagnosed with CFIDS among many other things- you name it- Lyme disease, "candida", so on and so forth. I had a doctor (well known) who dealt with what I would consider contraversial maladies who told me that the GS was not the source of my problems. Wrong, wrong.

I can tell you some of what has gone on with me. For instance, I have always had fairly low blood pressure (not too low, but low enough to evoke comments from the nurses who took my stats). I had also noticed throughout the years that I got tired fairly easily and that around my menstrual cycle I would have a bout of nausea. I was very intolerant of aspirin and became intolerant of sulfa drugs. Alcohol didn't agree with me at all.

In 1988, I had several events that happened all at once and I believe that they were what triggered a major attack that was to last 7 years. I had a flu virus, on top of which I wasn't getting any sleep at night, was taking Pepto Bismol (salicylates are a major NO for GS), had been not eating for long hours at a time (AKA dieting), and was taking a supplement called "Chromium".

I got sick all at once and had the following symptoms: nausea, backache, headache, cooking odors were offensive, totally no appetite, depression, intolerance to antibiotics which I had previously been tolerant to, extreme exhaustion, and what to me were "autistic" symptoms- couldn't stand loud noises, etc.

I have GS and I have a short of vit. B12 and my Fe level is very high

I was diagnosed 10years ago as having Post-Viral Fatigue Syndrome otherwise known as ME or Chronic fatigue syndrome and in the media as Yuppie Flu ou chronic Flu in america.

Tests came up with Gilberts Syndrome but they said it was nothing to worry about.

The symptoms were sudden... a sudden dizziness, brainfog, fatigue and later on I have had aches and pains after exerting classic ME symptoms.

The specialist i saw yesterday said that people with GS have a susceptibility to get ME/CFS.

As noone knows what ME really is perhaps it is just GS I dont know.

I actually wonder if many cases of CFS are actually GS. Before I was diagnosed I was wandering the net (after being told it was probably GF), and kept coming up with CFS - and it really seemed to fit the bill. With doctors thinking GS is benign are they not picking up this cronic fatigue as GS, and thinking it is CF

Alas, just a few weeks ago I was dismissively told I have GS. Ironically, tests they did about 7 years ago came up with the same results and I was not told - but there they were in my file. As the GP insists there are no symptoms, she is now sending me to a Chronic Fatigue Specialist.

PERSONAL: Gilberts Web Forums

The Gilberts is a marker for deeper toxicity issues that the doctors don't understand and / or won't acknowledge. If you have Gilberts Syndrome you are 4 TIMES more likely to get chronic fatigue. If you are still suffering after 2 years of good diet, no alcohol, milk thistle etc etc, then Gilberts is the marker for chronic fatigue. Investigate why you have chronic fatigue. This is a good starting point.

Yeasts & Mycoplasmas


The question of microbe interaction with hypercoagulable blood has been raised above. After viruses Mycoplasma are the smallest and simplest micro-organisms known. They have no cell wall and this allows them to invade tissue cells and replicate utilising the cells nutrients. When it becomes extra-cellular it takes a piece of the cell membrane with it and this can initiate an autoimmune process e.g. rheumatoid arthritis. According to Nicholson it can invade the Central Nervous System and NK cells. With induction of CD4+ cells Mycoplasma can trigger the release of the cytokines IL-1, IL-6 and TNF-alpha. Mycoplasma species are found in almost all body fluids and bone marrow as well.

In a study by Prof. Vojdani the following results were obtained using multiplex PCR tests.

  CFS(ME) n=100 CONTROLS n=100
Mycoplasma genus 52% 15%
Mycoplasma fermentans 32% 8%
Mycoplasma hominis 9% 3%
Mycoplasma penetrans 6% 2%

Prof. Nicholson has found similar results. He has also shown that multiple Mycoplasma infections are commoner in these illnesses. When he examined CFSME/FM patients for the presence of M.fermentans, M pneumoniae, M penetrans, and M hominis, he found multiple infections in over half of patients.

I must say though that after testing 70 patients for mycoplasma genus with PCR, I have only found 1 positive result. Why there is variance between different centres is not yet understood.

Oxidative Stress

Oxidative stress has a central role to play in this illness. In a paper published by Prof. Richards from Newcastle, Australia, it has been shown that oxidative stress, as measured by methaemoglobin, malondialdehyde and 2,3 diphosphoglycerate levels, was significantly raised in CFS/ME patients compared to controls. When comparing 33 patients against controls he found the following:

Blood parameter Mean control values Mean CFS (ME) values
Malondialdehyde 31.3 47.63
MetHb 0.62 1.45
2,3-DPG 5.07 5.73
Mean Red cell volume(MCV) 87.43 89.73

The amount of elevation correlated significantly with symptom expression in CFS /ME. His team felt that the mechanisms are similar to those found in rheumatoid arthritis. They also feel that bacterial toxins and Nitric Oxide can play a part in the elevated oxidative stress levels.

Prof. Pall has postulated that an excess of cytokines could cause a sustained increase in peroxynitrite levels. This is a potent free radical. The mechanism would involve cytokine induction of nitric oxide synthetase. This then causes an increase in nitric oxide levels, which reacts with the free radical superoxide to generate peroxynitrite. As peroxynitrite acts via six known biochemical mechanisms to increase the level of nitric oxide and superoxide, multiple amplification and feedback then occurs. This mechanism may be one reason for the high oxidative stress seen in this illness.

Following on from this is the important fact that peroxynitrite inhibits our anti-oxidant enzymes, Superoxide dismutase, Glutathione peroxidase and Catalase, again increasing oxidative stress. It is suggested that this increase in oxidative stress could cause damage to the hypothalamus and account for all the hormone problems. Also, high peroxynitrite and nitric oxide levels could account for the sodium channelopathies seen in this group of syndromes. Finally these high free radical levels would favour uncoupling of Krebs cycle oxidative phosphorylation in mitochondria. This could also lead to the abnormalities in urinary organic and amino acids as seen by McGregor.

Prof. Pall himself cites that there are twelve different observations on CFS(ME) and its symptoms that provide support for his theory

1 The level of neopterin, a marker for the induction of the inducible nitric oxide synthetase is elevated in CFS/ME.
2. Mitochondria are reported to be dysfunctional in CFS/ME. Also mitochondria are known to be damaged by peroxynitrite and by nitric oxide.
3. Both cis-aconitate and succinate levels are reported to be elevated in CFS/ME, and the enzymes that metabolise these two compounds are inactivated by peroxynitrite
4. The cytokines that can cause peroxynitrite elevation have been reported as being elevated in ten different studies.
5. These same cytokines have been reported to cause fatigue when injected into humans
6.An animal model(mouse) of CFS/ME has inducible fatigue after being exposed to a bacterial extract  that induces both inflammatory cytokines and inducible nitric oxide
7. Polyunsaturated fatty acid pools are reported deleted in CFS/ME and such polyunsaturated fats are known to be oxidised by oxidants such as peroxynitrite
8. Studies and anecdotal evidence has shown / suggested that antioxidants such as co-enzyme Q10, flavinoids and glutathione precursors are / may be useful in CFS /ME.
9. Women are reported to produce more nitric oxide than men do. A similar gender bias is seen in autoimmune diseases such as lupus.
10. Cases of CFS/ME are associated with high levels of deleted mitochondria DNA.
11. Biochemical similarities i.e. depletion of glutamine and cysteine pools have been reported in CFS/ME and several other disease characterised by elevated peroxynitrite.
12. Studies by other authors show high levels of oxidative stress in CFS/ME.

Prof. Pall feels that many of the clinical features of this illness can be explained in terms of oxidative stress e.g. infection induces nitric oxide which stimulates receptors that initiate pain perception. Nitric oxide has a central role in learning and memory and may be a partial explanation of the cognitive dysfunction in CFS /ME

Elevated Nitric oxide levels can also be linked to related conditions.

Exposure to organic solvents and pesticides, has been reported to precede Multiple Chemical Sensitivity and these induce nitric oxide synthesis and inflammatory cytokine production. Neopterin has also been found elevated in MCS as well as CFS /ME. In Fibromyalgia it has been reported that there is an excess of NMDA activity. This is known to increase nitric oxide and peroxynitrite.

In Gilbert's syndrome, i.e. unconjugated hyperbilirubinaemia, there is a four fold increased incidence in sufferers.  This also independently increases oxidative stress as well as having an impact on cellular uptake of thyroid hormones.

Professor Majid Ali from New York is a leading researcher in this field... He calls CFS/ME and Fibromyalgia, 'Oxidative – Dysoxygenative,' disorders.

In hypercoagulable states microclots and plaques measuring from 2-3 microns to over 40 microns can be seen. Also evident are many fibrin spicules, which are platelet derived. Embedded in the clots are platelet clumps and bacteria, and yeast like forms. Mycoplasma can also be seen. There is a correlation between the amount of abnormality and disease severity. Red cell shape abnormalities abound. The appearances are, according to Prof. Ali, a direct result of increased oxidative stress.

The overall result is an oxidative coagulopathy, where the microcirculation is clogged up producing:

1.Poor oxygen transport to cells
2.Poor oxidation in cells
3.The build up of organic acids causing acidosis

I now move on to the controversial topic of yeasts. Yeast- like organisms can clearly be identified through the video microscope. Again, only with phase contrast and magnifications greater than x8000. They appear generally after a few minutes and can be seen to spread across the field of view in yeast-like fashion. Majid Ali has extensively commented on the yeasts, their morphology and associations, with a detailed analysis of their growth patterns. There is a correlation between the amount of yeast – like forms and the rate of proliferation and severity of illness.

Incidence of yeast forms in Peripheral Blood of 100 patients with Fibromyalgia and or CFSME and 100 controls seen with High Resolution Phase Contrast Microscopy per 25 high power fields at 15,000x magnification

Incidence <3 4-9 10-14 >15
Patients 0% 12% 21% 67%
Controls 37% 54% 6% 0%

Frequency of Active Proliferation of yeast forms in peripheral blood of 100 patients with Fibromyalgia and/or CFS/ME and 100 controls expressed as a percentage of those germinating per 25 HPFs.

Germination rate <1 1-3 4-6 7 or more
Patients 6% 13% 28% 53%
Controls 7% 91% 2% 0%

Obviously, the presence of these yeast forms is not diagnostic. They seem to be another co-factor. Prof. Ali feels they are there as a result of an 'Oxidative regression to a primordial cellular state', an interesting and plausible explanation for the development of chronic ill heath. The growth of the yeasts is a direct result of the anaerobic/glycolytic pathway dominance in these patients.

He has also carried out a study that showed treatment with anti-fungals decreased the amount of yeast-like forms and improved symptoms. Symptom score 0 (no symptoms) to 4 (severe symptoms).

Symptom Pre-Treatment AfterTreatment
Fatigue 3.5 2
Myalgia 3 2
Cognitive difficulties 3.5 0.5
Malaise 3 1

he calls the ecological terrain existing in CFS/ME and Fibromyalgia an ‘Oxidative regression to primordial cellular ecology.’ In this state he feels we favour the overgrowth of latent microbes such as mycoplasma and chlamydia, as well as yeasts. They seem to be associated with erythrocytes. We already know that yeasts like Candida will use haemoglobin as a source of Fe. In summary they are only seen when oxidative stress exists.

Prof. Vojdani looked at serum from clinical cases, based on seronegativity or seropositivity for IgG, IgM and IgA autoantibodies against thyroid, adrenal and ovarian tissue. He then tested each sample for the presence of Candida antibodies. Expressed as a percentage expressing Candida antibody overall:

Seropositive for autoantibodies  - 60% had Candida antibodies
Seronegative for autoantibodies  -7.5% had Candida antibodies
Controls - 10% had Candida antibodies

Confirmatory evidence came from the fact that when antibody positive tissue was treated with rabbit anti-Candida antibodies and human positive sera, it produced a reduction in thyroid autoantibody levels.

When talking about thyroid antibodies researchers found have those thyroid antibodies can disappear after 3-6 months on a gluten free diet.

However, an excess of hsp's can have deleterious effects. Too many inhibit protein folding and increased levels may be seen as dangerous or foreign antigens by the immune system. Studies in the past have shown that because all hsp's are very similar genetically, they can trigger autoimmune states, such as in leprosy, TB and Histoplasmosis by cross reactivity between the infective agent hsp's and human hsp's.

Candida produces several hsp's. The important ones in this story are hsp 47, 90 and 70. These Hsp's are involved in hormone action. They are required to fold steroid hormone receptors until the steroid hormone binds to the receptor. But, in candidiasis, an excess of hsp 47 effectively blocks this action. People who survive deep-seated Candidiasis make a lot of antibodies against hsp 47. Also, another very important fact is that peroxynitrite has been shown to be a strong stress to human monocytes, leading to a dose dependent increase in hsp 70.

When discussing upregulation of the 2-5 Synthetase/RNase L system you will recall Vojdani showing that this can be induced by MTBE and benzenes in the presence of hsp 70. Is it therefore, the cross reactivity between hsp from the yeasts, and human hsp's with the immune system that is contributing to the clinical picture? The more yeasts seen on microscopy, the sicker you are. It would help to explain not only the upregulation of the RNase L enzymes, be they normal or low molecular weight, but the hypercoagulable state found in patients, and also steroid hormone resistance, which I see a lot of.

Bacterial Overgrowth

Many CFS sufferers, myself included, report an improvement while on antibiotics. While temporarily reducing the pathogen in question, beneficial bacteria populations are also being systematically eliminated, forever perpetuating the vicious cycle.
Diagnosed with Chronic Fatigue Syndrome one year ago I am now convinced that most all of my symptoms were a result of an overgrowth of Citrobacter freundii identified by your lab (GSDL) in December 1996. Chronic sinus infections treated with six antibiotics proved ineffective and only sterilized my intestinal tract of friendly bacteria.(Bactrim, Lorabid, Zithromax twice, Biaxin, Augmentin) By the time I took the correct antibiotic Cipro, as suggested by your sensitivity chart, the bacteria was so entrenched that a ten day dose could not eradicate this pathogen.

I speak from experience when I say that this bacteria can be devastating to ones health. It feeds on sugar and is capable of leaving the intestinal tract taking up residence in the mucus membranes of the sinus and lungs. A severe respiratory infection could not be treated with yet another antibiotic in February of this year. Fortunately intravenous hydrogen peroxide arrested its progress.

Eliminating sugar from the diet similar to the anti-candida diet and taking citrus seed extract has proven to be most effective in controlling the growth of this bacteria. Any cheating whatsoever on the sugar intake proves disastrous. A recent follow-up CSA shows a reduction of the pathogen from previous levels. Adding close to 100 billion Acidophilus and Bifidus bacteria per day for the past two months has increased the levels of healthy bacteria shown on the CSA results.

The point I'm trying to relay here is the seriousness of this pathogen and what it is capable of. Which takes me back to the attached file concerning the use of Citrobacter freundii in a probiotic bacterial culture administered to young chicks to competitively inhibit Salmonella bacteria in their intestinal tracts. Why would the USDA approve one pathogen to replace another?

I am convinced that it was this bacteria that was responsible for my Chronic Fatigue Syndrome. The bizarre symptoms associated with this illness are a result of the toxins released after the microorganism dies.

Q: How strong was the Citrobacter Freundii on your CDSA? (Mine was just 1+.)
A: My test results showed Citrobacter freundii was at a level 4+ and like yourself, NO lactobacillus! Four months later Citrobacter freundii was still present at 1+


Diagnosing CFS

In addition to the official researchers' definition discussed below, patients and experienced clinicians have noticed symptom patterns that seem prominent in CFS. These include the observations that cognitive dysfunction often increases over time (over several years), and that brain scans often show that blood flow to the brain is decreased. CFS is defined somewhat differently by various medical groups in different countries. The 1994 research definition published by the U.S. Centers for Disease Control and Prevention recommends a step-wise approach for identifying CFS cases. The first step is to clinically evaluate the presence of chronic fatigue, i.e. "self-reported persistent or relapsing fatigue lasting 6 or more consecutive months".

Conditions that explain chronic fatigue should exclude a diagnosis of CFS. These are:

- "any active medical condition that may explain the presence of chronic fatigue ..." - any previous condition which might explain fatigue and which has not documentably come to an end; - "any past or current diagnosis of a major depressive disorder with psychotic or melancholic features; bipolar affective disorders; schizophrenia of any subtype; delusional disorders of any subtype; dementias of any subtype; anorexia nervosa; or bulimia"; - substance abuse within 2 years prior to onset; - severe obesity.

The following should not exclude a diagnosis of chronic fatigue:

- conditions which cannot be confirmed by lab tests, "including fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or nonmelancholic depression, neurasthenia, and multiple chemical sensitivity disorder"; - any condition which might produce chronic fatigue but which is being sufficiently treated; - any condition which might produce chronic fatigue but whose treatment has already been completed; - any finding which on its own is not sufficient to strongly suggest one of the exclusionary conditions.

After the above criteria are met, the following core criteria for CFS are applied: "A case of the chronic fatigue syndrome is defined by the presence of the following:

1) clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (has not been lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social or personal activities; and
2) the concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue:

- self-reported impairment in short term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social or personal activities;
- sore throat;
- tender cervical or axillary lymph nodes;
- muscle pain;
- multi-joint pain without joint swelling or redness;
- headaches of a new type, pattern or severity;
- unrefreshing sleep;
- and post exertional malaise lasting more than 24 hours."




Avoid stress

As odd as it may seem, typically the most beneficial program is for the patient to avoid stress and to get lots of rest. This is usually the most effective regimen, among others that might also be undertaken. Stress does not merely mean unpleasant experiences, but rather any biological stressors, physical or emotional, which prompt a protective reaction in the body and which may alter physiologic equilibrium ("homeostasis"). Failure to avoid stress often leads to short-term and long-term set-backs which may be serious. Many patients believe that if they had done more to avoid stress in the early phases of the illness, they would not have become nearly so disabled later on. The correlation between stress and the progress of this illness appears to be strong.



Treatments tend to address the symptoms, since the underlying mechanism of the disease is not really understood. Medications which are helpful are often those which have immune-modulating characteristics. CFS patients are unusually sensitive to drugs and they usually must take doses that are 1/4 or less than standard doses. Some drugs will be a big help to some patients and little or no help to others. And drugs that seem to work for a while may stop being effective later.

According to studies presented at the October 1994 CFS medical conference, widely used treatments included: SSRIs ("selective serotonin re-uptake inhibitors" such as Zoloft, Paxil and Prozac) used to address fatigue, cognitive dysfunction and depression; low dose TCAs ("tricyclic anti-depressants" such as doxepin and amitriptyline) for sleep disorder, and muscle and joint pain; and NSAIDs ("non-steroidal anti-inflammatory drugs" such as ibuprofen and naproxen) for headache, and muscle and joint pain. Other treatments often prescribed are Klonopin, intra-muscular gamma globulin (IMgG), nutritional supplements (particularly anti-oxidants, B-vitamins generally and B-12 specifically), herbs, and acupuncture. Less often prescribed were chiropractic therapy, intra-muscular gamma globulin (IVgG), kutapressin, antivirals, interferon, and transfer factor.

Research from Johns Hopkins University in 1995 indicate that treatment for neurally mediated hypotension may be effective for the many CFS patients who may show positive for that condition.

These can help if testing reveals overgrowths. I normally use a combination approach. Nystatin* can help in gastrointestinal Candida, and in cases where a leaky gut is suspected, at a dose of 1 or 2 tablets four times a day for two to six weeks. I use Fluconazole* 50gs once daily for one week with Terbinafine* 250 mgs per day for two weeks initially, although this can be extended.


This is converted into cortisol directly. Dose range is 2.5 mg (Corlan Pellet*) to 15 mg in divided doses, (4mg of hydrocortisone = 1mg of prednisolone). Safety studies have been carried out which indicate that up to 25 mgs does not suppress endogenous ACTH.

For women use10 mg bd., and in men 25mg bd. Conversion of DHEA to extra oestrogen and testosterone does not occur significantly until > 50 mgs daily.

Use 0.5mg at 8-9pm. This helps to initiates sleeps via the Histamine-Interleukin-Prostaglandin system. Melatonin is the 'molecular manifestation of darkness'. It may be possible to reset the internal body clock with about 4-6 months treatment.

Thyroid replacement*
This is useful in clinically hypothyroid patients with low/borderline levels, and especially if autoantibodies are present. Aim to keep T4 and T3 within the reference interval.


Role of Exercise

CFS patients will need to avoid stressful activities, and each patient's toleration for stress will be different, and can change). It is nonetheless important for patients who can exercise to do so, up to their level of toleration. But this should be done with great care, since crossing the "invisible line" of exercise intolerance for this illness may prompt a serious relapse, and may negatively affect the longer-term future course of the illness.


The typical American diet continues to feed this bacteria which makes it stronger and virtually impossible to eliminate since it is a glucose fermenter. Complex sugars from carbohydrates and starches will allow this pathogen to proliferate, mutate and become even stronger. The only relief to this cycle is to eliminate its food source as I have done. Following the Gottschall diet "Breaking the Vicious Cycle" gave immediate results.

Note: The "Specific Carbohydrate Diet" described in Gottschall's book is a variety of low-carb diet. Many different low-carb diets have been beneficial to those with Gilbert's Syndrome.

Food choices are very important. In general, a glycaemic diet should be followed (a protein to carbohydrate ratio of 1:2 by weight or calorie counting as they are calorie equivalent), with good quality proteins and slowly digested carbohydrates. Organic food is preferable, but still expensive. Dairy and gluten avoidance helps some people and research is under way at present on this.

Dietary Changes

CFS patients appear to be alcohol intolerant. Other food products often recommended against include caffeine, sugar and nutrasweet. Since in many patients it appears that the immune system is over-active, it may be more important than usual to take nutritional supplements to replenish burnt up reserves.

Many patients have or develop food sensitivities, and in these cases relief may be found by avoiding foods that prompt problems. Patients tend to gain weight and they don't have vigorous exercise available as a counterbalance, so diet needs to be monitored with this in mind.

Supplements, Minerals & Vitamins

Vitamins / Minerals and Nutritional Supplements

1. A good antioxidant /mineral mixture
They should contain a balance of both fat and waters soluble vitamins, include selenium, and be taken all the time. Oxidative stress can be measured using blood methaemoglobin, or Vespro's Free Radical Test kit which measures urinary malondialdehyde levels. This is an easy to use kit based on a visual colormetric scale. Supplement levels should be adjusted until normal ranges are achieved. These should be checked periodically at around monthly intervals. It is particularly important to get this right before anti-fungals are taken to prevent die-off reactions.

2. B Vitamins*
Poor functional levels of B Vitamins have been reported by Heap et al using AST, glutathione reductase, and transketolase as markers of pyridoxine, riboflavin and thiamine respectively. (P< .001). Compounds with up to 50mgs of each per day can be used.

Low levels of B12 are found in the cerebrospinal fluid of patients, reflecting poor neuro-axis levels. High CSF levels of homocysteine are also found. B12 deficiency causes deficient remethylation of homocysteine. Indeed Low brain levels have been associated with many degenerative neurological disorders. It is thought that B12 couples with environmental toxins in an attempt to detoxify the brain... B12 also acts as a nitric oxide scavenger helping deal with excessive oxidative stresss.

3. Magnesium malate*
1000mgs once a day – used in the Teitelbaum study. This is good for muscle physiology. Also, Dr. David Dowson published a double blind study in 1991 showing low red cell magnesium levels in CFS/ME patients which improved with treatment, as did symptoms in patients.

4.Folic acid*
5mg once daily. Some patients need very high doses. Again abnormalities in folic acid metabolism are common.

5. Oral NADH (Enada)
Recommended dose is 5-10 mgs / day. The reduced form is absorbable orally. Nicotinamide adenine dinucleotide is used in ATP production. In a double blind crossover study, 26 patients were given oral NADH at a dose of 10 mgs per day. On active treatment 31% responded favourably against 8% on taking placebo.

6. Undenatured whey proteins (Immunocal* Imuplus* Immune Pro *Solgars Whey To Go*)
Basically, these are milk-derived products, which are very close biochemically to human breast milk. They have anti-viral, bacterial and possibly fungal action. They contain two cysteine molecules bound together, which is a requirement for absorption. This is an essential precursor for glutathione. Low glutathione levels are seen in patients, particularly in white cells. It has been shown to raise glutathione levels

It wasn’t until I was introduced to Dr. Jack Larmer ND on Nov. 14, 1997 that this constant struggle came to an end.

Dr. Larmer’s approach was to change the environment so it is not conducive to the overgrowth of pathogens. His method of treatment spans forty five years of experience.

I mix a drink in the morning using apple cider as a base liquid along with the juice of a freshly squeezed large lemon. Included in this drink is a variety of intestinal clensers, concentrated liquid ionic minerals, oxygenating cellular formula, live enzymes, amino-acids, anti-oxidants, essential fatty acids, phytochemical rich herbs, and other natural ingredients. Along with this drink he has included support for the liver, pancreas, thyroid and adrenal glands.

-Amylase breaks down starches
-Protease breaks down proteins
-lipase breaks down fats


Wherever possible I start with natural methods and increasingly use olive leaf extract and a probiotic/real food liquid  called ‘Before everything’ followed Prime Directive to heal the gut in every patient. Olive leaf is an immune booster and the probiotics contains 12 species of lactobacilli, 2 saccromyces species, enzymes, whole foods and micronutrients.

Instead of trying to shoot the bacteria with that magic bullet, why not fight bacteria with bacteria. Not just any bacteria but a specific group designed to devour any pathogen and restore that environment to healthy status.

I believe that I am now taking the correct combination of beneficial bacteria in sufficient quantities necessary to reestablish healthy populations. I began taking these capsules (Nature's Biotics 1-800-713-3888) on Saturday Jan. 10Th and within the hour experienced "Herxheimer reaction" (die-off) lasting most of the morning.
This die-off has been experienced with natural substances as reported in my previous email. This is the first time a group of beneficial bacteria has produced this effect. My past experience with die-off was an indication that a substance was effective. I will keep you informed of my progress.

The following list of symptoms are experienced when the bacteria is no longer kept under control by natural agents:
1. loose stools/ steatorrhea (yellow diarrhea)following meals
2. Lightheaded/shortness of breath
3. Fatigue/weakness
4. Anemia
5. Sinus congestion
6. Lung congestion/mucus
7. Chest pain on right side
8. Stiff neck
9. Sleep disturbance
10.Brain fog/memory loss/loss of words
I have experienced “Herxheimer reaction” (die-off) with the following natural agents (Level of die-off):
1. Entrocaps (berberis/grapefruit seed extract) Severe
2. Black walnut extract capsules: Moderate
3. Uva Ursi capsules: Severe
4. Clove raw: Slight
1. Black walnut extract/39-44% grain alcohol *Severe
2. Wormwood extract/70-75% grain alcohol *Severe
3. Ginger extract/72-78% grain alcohol *Severe
1. 3% hydrogen peroxide (ingested): Slight
2. Pau D`Arco tea: Slight
3. Liquid grapefruit seed extract: Moderate
4. Colloidal silver: Unknown

Here is an explanation of "die-off"

Toxins are released when bacteria die. These toxins are absorbed into the blood stream and overwhelm the liver and its filtering capability. Bacteria die every 20 minutes. When bacteria die in large numbers symptoms worsen. A temporary toxic reaction does occur. The technical name for this experience is Herxheimer reaction

Drew: My pH is 7.8.
Carl Tuttle: 7.8 pH is far too alkaline for aciddophilus to survive.
Drew: Interesting ... my CDSA reported Lactobacillus is 0+ (though Bifodobacterium is 4+).
Carl Tuttle: Acidophilus means "acid loving" Dr. Larmer prefers a slightly acidic environment. One way to acidify the gut is to squeeze the juice from one large or two small lemons into six ounces of water, heat in the microwave for one minute, add one dropper of ginger extract. I took this twice per day.

Bacillus subtilis can eat a lot of harmful bacteria.

Taking various natural substances allowed me to keep this pathogen somewhat under control although never eliminating it completely. Over time the bacteria developed resistance to each and every agent (grapefruit seed extract, black walnut extract, uva ursi, ginger extract, wormwood extract).


I myself am not convinced of the efficacy of this. The first three days I had yogurt a few months after my course of antibiotics I felt incredibly improved, almost cured. But then it stopped having any effect - in fact for the rest of the month that I was eating yogurt and taking probiotics daily, it caused a food-coma like reaction- fatigue and brain fog. I thought this was a sign of die-off, but that appears to be a tautology of sorts. If it makes you feel better, it's working. If it makes you feel worse, it's working. Under what condition is it not working? For me that was that there was no improvement after a month. It appears in the end that Carl came to a similar conclusion. Although he still recommends probiotics on his web site.


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