The cause or causes of CFS are still not clear. There are a number of theories that have been proposed, the main ones propose the following factors as the cause or causes of the illness:

• Viral Infection
• Mycoplasma Infection
• Immune or Endocrine Dysfunction
• Autonomic Nervous System Dysfunction
• Environmental Toxins
• Genetic Factors
• Candida Overgrowth/Gut Dysbiosis
• Heavy Metal Sensitivity
• Emotional Stress or Trauma

Viral Infection

For a long time it was thought that chronic Epstein Barr Virus (EBV) infection was the sole cause of CFS but this theory has lost support as research has shown CFS to be a much more complex illness. Recent studies are still finding a link to EBV however, at least in a subset of patients (1). There are studies ongoing into other possible viral causes, Human Herpes Virus 6 (HHV-6) has often been detected in the blood of CFS patients and has attracted a lot of attention in the past but some recent studies have failed to find a link (2, 3).

Despite inconclusive research findings with respect to specific viral causes for CFS, it is still thought by many that a dysfunctional immune response to viruses and chronic viral infections are at the heart of the condition. One key piece of evidence for this position comes from the finding that CFS patients have abnormalities of RNase L. RNase L is an enzyme found in every cell in the body which is activated within a particular cell when it comes under attack from viruses, and to a lesser extent bacteria and some toxins. The job of RNase L is to take care of the threat from invading viruses by destroying their RNA or by signaling an already infected cell to die, taking the virus with it. It has been found in numerous studies that CFS patients have fragmented RNase L and the RNase L system as a whole is dysfunctional. As a result the patient has compromised defences against viral infection. The RNase L abnormalities are seen as the closest thing to a biomarker for CFS currently available as the findings are so consistent.

Mycoplasma Infection

There is substantial evidence for mycoplasma infection playing a role in CFS. Mycoplasma can be defined as the smallest organisms lacking cell walls that are capable of self-replication and can cause various diseases in humans. Although usually associated with respitory and urinary disease, mycoplasma are thought by a growing number of medical professionals to be responsible for a number of unexplained symptoms, especially chronic fatigue states. Mycoplasma fermentans has been found in the blood of CFS patients at a much higher rate than in the overall population.

"Although mycoplasmas are recognized primarily as extracellular parasites or pathogens of mucosal surfaces, recent evidence suggests that certain species may invade the host cells.

The molecular and cellular bases for the invasion of M. fermentans from mucosal cells to the bloodstream and its colonization of blood remain unknown.

Also, it remains unclear whether M. fermentans infection of white blood cells is transient, intermittent or persistent. It is not clear how these stages influence any disease progression. The invasion of host blood cells by M. fermentans is due to inhibition of phagocytosis by a variety of mechanisms, including antiphagocytic proteins such as proteases, phospholipases and by oxygen radicals produced by mycoplasmas."

Immune Dysfunction

CFS has long been considered to be an illness of immune dysfunction and there is ample evidence that considerable immune dysfunction is present in patients. Immune activation is a global finding with a range of specific abnormalities present in significant numbers of patients. The most common of these include elevated T lymphocyte numbers and elevated circulating cytokines (immune signaling chemicals). Despite this, immune cell function of CFS patients is poor, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3 (4). Another finding is that the immune system of CFS patients is unbalanced, with T-helper cells of type 2 heavily outnumbering those of type 1 (5). Th1 cells stimulate immunity directed at organisms which invade cells, such as viruses whereas Th2 cells stimulate immunity targeted towards invaders found outside of cells such as bacteria, parasites, toxins and allergens. This finding could certainly explain the fact that CFS sufferers have a higher occurrence of allergies than the healthy population. It also provides a reason why CFS patients may have chronic viral infections as immunity is directed away from protecting against them.

Endocrine Dysfunction

Much research has centred around the endocrine system of CFS patients. Particular interest has been paid to the hypothalamic-pituitary-adrenal (HPA) axis which is responsible for the stress response. A number of abnormalities have been observed in CFS patients with regards to this including low cortisol and DHEA sulphate levels as well as altered melatonin metabolism (6). Cortisol and DHEA-S work in synergy to control how the body reacts to stress. Low levels affect your ability to deal with stress and can cause fatigue, low blood pressure, hypoglycemia, poor brain function and a number of other problems common to CFS sufferers. Melatonin is a hormone whose main action appears to be to induce sleep. During the day the pineal gland, stimulated by light signals the body to produce serotonin and other chemicals to 'wake the body up'. When light levels fall the pineal gland signals the production of melatonin in place of serotonin, preparing the body for sleep. If melatonin production is disturbed as it has been seen to be in CFS then this can cause disruption to sleep as is commonly seen in CFS patients. Adding weight to this hypothesis is the fact that low doses of hydrocortisone (cortisol) have been shown to improve symptoms in a number of studies (7, 8). Many physicians also prescribe DHEA and melatonin in low doses for their patients and many find that they are of great benefit.

Autonomic Nervous System Dysfunction

One common problem in CFS that is often overlooked is a feeling of dizziness, weakness and feeling lightheaded upon standing. Studies have confirmed that a majority of CFS patients have what is known as neurally mediated hypotension (NMH) (9,10). This means that when CFS patients stand up or exert themselves (especially walking up hills or climbing stairs) their blood pressure can drop dramatically. When a healthy person carries out these activities the autonomic nervous system automatically increases output of adrenal hormones (corticosteroids, adrenalin etc) which in turn cause the heart to pump harder and blood pressure to increase. In CFS this often doesn't happen correctly so there is a lack of bloodflow to the head and the symptons described above result. Researchers and doctors are now trying to treat NMH in CFS patients where it is identified. Research has centred around administering small doses of corticosteroids to provide the body with the amount it should be producing by itself. Results so far have not been favourable but research in this area is ongoing (11, 12). Despite the failure of these studies to see an improvement using low dose corticosteroids a number of doctors specializing in CFS are adament that this treatment benefits a subset of their patients where definate NMH is present. Many doctors treating CFS also recommend dramatically increasing salt and water intake to help increase blood presure and reduce NMH related symptoms.

Both CFS and fibromyalgia patients suffer from strange cognitive difficulties. Often feeling overwhelmed by sounds, smells and other sensory information, especially when in busy public places such as a mall or office. Skin often feels very sensitive to the touch as well. Dr. Jay Goldstein believes these and the other symptoms of CFS can be explained by neurological dysfunction. When the brain receives sensory information such as this, the prefrontal cortex decides on the importance of the information before passing it on to the rest of the brain for processing. In CFS sensory information that should be classified as low importance is given high importance. As a result, the brain is overwhelmed by all this "important" information all at once and the patient feels overwhelmed and exhausted. At the root of this information processing problem may be deficiency of certain neurotransmitters, most importantly glutamate, norepinephrine and dopamine.

Environmental Toxins

There is a large proportion of CFS patients who complain of everyday amounts of volatile chemicals triggering or worsening symptoms, i.e. multiple chemical sensitivity (MCS). This has led some researchers to look down this path for answers to the CFS puzzle. One study quotes the rate of severe chemical sensitivity amongst CFS patients at 20%-47% (13). The same study provides compelling evidence that the limbic system (the emotional centre of the brain) of susceptible individuals can become sensitized by chemical, biological and psychological mechanisms and that subsequent exposure to stimuli can cause disregulation of multiple body systems including behavioral, autonomic, endocrine, and immune system functions. Animal models have shown that sensitization can occur as a result of chronic exposure to everyday amounts of volatile organic chemicals (VOC's). In addition to these findings there is also strong evidence of abnormalities of detoxification in CFS. Glutathione, the body's most powerful antioxidant, is consistently found to be low (14, 15). Glutathione may become depleted due to chronic exposure to high levels of toxins. This could potentially be as a result of exposure to toxins in the air or from chemicals of gut origin in the presence of gut dysbiosis. Overactivation of the immune system also depletes glutathione so this may come as a knock on effect from immune system abnormalities. What is certain is that low glutathione leads to fatigue and muscle weakness and pain due to its role in energy metabolism. Low glutathione also results in oxidative stress, meaning that highly reactive oxygen molecules are not neutralized and are thus free to roam the body damaging cells and interfering with potentially any body system.

Genetic Factors

Genetics can be said to be a factor of varying importance in the development of any illness. Consistent with this statement, a number of possible areas of genetic susceptibility have been identified for CFS in various studies. One such study involving twins with CFS and healthy control twins found that the CFS group had much slower reaction times on all speed related cognitive tests. The researchers postulated that this indicated a central information processing deficit in the brain (16). This finding illustrates one theory about the pathogenesis of CFS best described by Dr. J. Goldstein. Dr. Goldstein has treated thousands of CFS patients based on his theory that their brains process sensory information abnormally as a result of certain neurochemical deficiencies. Other research, also centered around brain function, found that CFS patients have differences in genes responsible for serotonin production which leads to lower reservoirs of serotonin, the chemical responsible for maintaining positive moods and also healthy sleep cycles, amongst other functions (17). Finally, a study again using twins, found evidence of immune dysfunction indicating a possible genetic susceptibility (18).

There have been two genetic studies recently that have been hailed as major advances in understanding chronic fatigue syndrome:

The first hit the headlines in July 2005. It suggests that gene expression, the pattern in which genes are switched on and off' is significantly different for certain genes in those with CFS. Researchers at Imperial College, London, looked at the way genes are activated in immune cells of 25 CFS patients and 25 healthy controls. They initially found 35 genes that showed differences while more precise examination revealed 16 that showed definite and significant abnormalities. The lead researcher, Dr Jonathon Kerr suggests that the results support the theory that the illness is often triggered by a virus, namely those discussed previously on this page. Many of the genes that were identified affect the functioning of the mitochondria, the energy generating plants within cells. As such, the abnormal gene expression could account for symptoms of fatigue and lack of energy. The energy producing mitochondria within patients cells may literally be not producing enough energy. The team behind the research hopes to run a much larger study of 1000 patients in the future and it is hoped the research will lead to reliable diagnostic tests for CFS and to new treatment approaches.

The second study, the largest ever to focus on CFS, was completed in 2006 and provided the results that the CFS community has been waiting for. Dr. Julie Gerberding, director of the Centers for Disease Control (CDC) said at a press briefing “It really is the first credible evidence of a biological basis for chronic fatigue syndrome.” The study involved 227 CFS patients and was conducted in Wichita, Kansas at a cost of $2 million. The study volunteers spent two days in hospital undergoing detailed clinical evaluations including sleep studies, cognitive functioning measurements, autonomic nervous system evaluations, extensive blood work and genetic testing. The activity levels of 20,000 genes were assessed and it is here where the really groundbreaking findings were discovered. At the press briefing, Dr. Reeves, the lead CFS researcher at the CDC, stated “For the first time ever, we have documented that people with CFS have certain genes that are related to those parts of brain activity that mediate the stress response. And that they have different gene activity levels…that are related to their body’s ability to adapt to challenges and stresses that occur throughout life, such as infections, injury, trauma or various adverse events.” What this means is that people with chronic fatigue syndrome generally have a lower tolerance to these various stressors. The result of this is that in people predisposed to CFS, their bodies can become overwhelmed by events that other people would be able to shrug off, and this is where dysfunction in various body systems such as the nervous, endocrine and immune systems sets in. The researchers at the CDC went on to say that they identified a number of different subgroups within the patients tested, verifying what many had suspected, that CFS isn't a single easily identifiable disease with a single cause and diagnostic marker, but rather the result of a complex disease process. They also stated that this research proves once and for all that CFS is a very real biological disease and hope that it will lead to better diagnosis and treatment in the near future.

Gut Dysbiosis

Around 30 years ago a handful of physicians, most notably Dr's Crook, Truss and Trowbridge described a syndrome characterized by a wide range of symptoms very similar to those of CFS which they suggested was caused by overgrowth of the normal intestinal yeast such as Candida albicans which proliferated due to antibiotic usage and other factors. They treated their patients with antifungal drugs with reportedly good results. A small amount of subsequent research seems to validate their theories with it becoming clear that antibiotic drugs adversely affect intestinal flora and allow Candida sp. to become prevalent (19, 20). There are studies that appear to show successful treatment of intestinal candidiasis with antifungal drugs as well (21, 22). Strangely, although Dr. Crook in particular connected intestinal yeast overgrowth with CFS decades ago there has been little material published regarding this since, apart from a few papers again suggesting the link due to the observed similarities between supposed yeast related illness and CFS (23). The most likely reason for this is the still pervasive view that there are no definitive tests for intestinal yeast overgrowth. Testing of urine or blood for 'tartaric acid' would appear to offer just this definitive test however. Tartaric acid is a product solely of yeast and is not produced as part of human metabolism, therefore any detected in blood or urine must have originated from the yeast that inhabit the intestinal tract. Studies could, and should, be undertaken to compare tartaric acid levels between healthy controls and patients with CFS. Patients of all the illnesses on this site as well as other unexplained chronic illnesses should also be tested to establish the role of yeast overgrowth in these conditions. An important study recently published has shown the link between antibiotic alteration of gut flora, candida proliferation and the initiation of allergic illness (24). Since allergies are prevalent amongst CFS sufferers this research is further evidence that the link between CFS and intestinal yeast should be investigated. Despite the lack of published research, all the major diagnostic labs that serve functional/integrative medicine physicians consistently report a correlation between yeast markers such as tartaric acid, elevated blood ethanol and Candida antibodies in samples from CFS patients. A large number of physicians specializing in the treatment of CFS and related illnesses include anti-fungal agents as a major part of their treatment protocols. A search of online forums, chat rooms and blogs also reveals a large number of CFS patients who have had success self-treating with an anti-fungal protocol. Further research in this area is long overdue.

With more published research behind it is the idea that small bowel bacterial overgrowth (SBBO) might play a role in fibromyalgia (15). This is something that has been extensively connected with irritable bowel syndrome in recent years (26) and as CFS and IBS are commonly diagnosed in the same individual, it offers another avenue of potential treatment. SBBO can be treated with targeted antibiotic drugs or with antibiotic herbs.

'Leaky gut syndrome' is thought to be a result of gut dysbiosis and food allergies, amongst other things, and could contribute to the disease process in CFS and a number of other chronic illnesses.

Heavy Metal Sensitivity

A surprising amount of published research indicates a role for heavy metals as causative agents in CFS. One study using CFS patients and healthy controls found that the CFS group had significantly higher serum levels of aluminium at the expense of iron (27). The researchers correlate this low iron level with low DHEA which has we have previously mentioned as a common finding and possible contributor to symptoms in CFS patients. Another research group found an increased incidence of nickel allergy in CFS patients compared to control subjects. They suggest that immune activation by nickel or cross-reacting metals could be an etiological factor in CFS (28). Mercury amalgam dental fillings are often cited as a possible cause of chronic illnesses and there is published evidence that this may well be the case, although specific research with CFS patients appears to be lacking (29).

Emotional Stress and Trauma

It has been suggested that a significantly high proportion of CFS patients have a "Type A" personality. This means they are highly driven people who put a lot of pressure on themselves and need to be the best and first at everything and hate to make any mistakes, basically they are perfectionists. This has led a lot of people to speculate that stress and its effects on the functioning of the brain are at the root of the illness. This theory is strengthened by the evidence discussed above regarding dysfunction of the HPA axis and stress response in CFS sufferers. Stress also has deleterious effects on the immune system so it may be that people with a stress prone personality are more at risk from opportunistic infection or other disease causing factors.