ME/CFS pathophysiology

The pathogenesis or the mechanisms and processes of Chronic fatigue syndrome (CFS) are gradually being revealed through research, including physiological and epidemiological studies. In a basic overview of CFS for health professionals, the CDC states that "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness."

Chronic fatigue syndrome (CFS) or (ME) has been described in a 2008 Toxicology journal article as, "a constellation of multi-system dysfunctions primarily involving the neurological (nervous system), endocrine (hormone system), and immune systems." The article states recent research suggests the potential that xenobiotic (chemicals), infectious agents, stress, and other insults in early-life may be a component of later-life CFS.

Pathophysiology (1) Immune system, Infection
A 2007 article in the journal Autoimmunity summarised; “The current concept is that CFS pathogenesis is a multi factorial condition in which an infective agent cause an aberrant immune response characterized by a shift to Th-2 (cytokine) dominant response. When the response fails to be switched-off, a chronic immune activation occurs and is clinically expressed in the symptomatology of CFS."

Immune dysfunction
When compared with CFS patients with normal natural killer cell activity, a 2006 study found those with lower levels reported less vigor, more daytime dysfunction, and more cognitive impairment; with the researchers suggesting this to be useful at subtyping. A systematic review on the immunology of CFS (published in 2003) found an inverse association between study quality and findings of low levels of natural killer cells (suggesting that the association may be related to study methodology), although no such association was found with studies finding abnormalities in T cells and cytokine levels. In 2006 an updated review on the phenomenology and pathophysiology of CFS found that, "immune system involvement in the pathogenesis of CFS seems certain but the findings on the specific mechanisms are still inconsistent." There is also evidence that people with CFS have improper gene expression including both over expression and under expression of genes involved in the immune system (see the gene expression section).

RNase L deregulation
Several studies have detected an abnormal form and activity level of 2-5A synthetase/RNase L enzyme (antiviral immune response) in some CFS patients   that appears to correlate with a reduction in exercise capacity,  and daily functioning. A review published in 2005 suggested that this impaired pathway is of clinical importance and that further studies addressing treatment of this deregulation are warranted. A study found that elevated RNase L did not correlate with alpha-delta sleep.

Hyperactive immunity
Autoimmune disorders, representing a hyperactive immune system, most likely through a cell-mediated process, have been suggested. In July 2005, researchers in the UK reported significant gene changes in the white blood cells in CFS patients consistent with the theory of immune system activation, possibly by an antigen triggering a constant immune fatigue state. The study, led by Dr Jonathan Kerr, discovered that 35 white blood cell genes, out of a total of 9,522 genes scanned were demonstrating differential function. There was also suggestion of neuronal and mitochondrial dysfunction as a result.

Allergies
Patients with CFS commonly develop additional problems with allergies or food intolerance.

Immunodeficiency
Immunodeficiency disorders (underactive immune system) have been reported. In 1989, an Australian study documented a loss of immunological integrity in one hundred CFS sufferers. The authors found disordered ratios of T-cell subsets and reduced levels of immunoglobulins specifically IgG 1 and IgG 3; there have since been other similar findings,   and a review Most strikingly, using the French Multitest to measure the body's response to a variety of antigens, the Australian group found that 33% of the subjects were hypoallergic, meaning they had a reduced immune response to the tested antigens, while an additional 55% were completely anergic (no immune response to the antigens).

Cytokine pattern
Cytokine pattern; several studies  and a number of reviews    indicate there is a cytokine pattern of type 2 response including Th2 T helper cell, bias in CFS. This promotes the humoral immune system which stimulates B cells and increases antibody production. It is suggested that this explains some immune dysfunctions in CFS. A reduction in Th1 response has also been found in some CFS studies. with implications for altered Th1/Th2 balance. Therapeutic interventions aimed at induction of a more favorable cytokine expression pattern and immune status are being investigated.

Enteroviruses
Often, there is evidence of enteroviruses, e.g. the Coxsackie virus. The type of enterovirus varies, which can affect symptoms. Polio virus is one enterovirus associated with ME, in earlier times of outbreaks, before polio vaccination was common, paresis (paralysis) was often found in ME patients; this is no longer the case. Stomach biopsies of 80% of CFS patients showed the presence of enteroviruses in one study, as opposed to only 20% among controls, and nearly all biopsy specimens had microscopic evidence of mild chronic inflammation. Hyde and others suggest that these enteroviruses had been latent to be awakened by another, triggering infection, after which the immune system stays chronically active to combat the enterovirus.

Reviews report different laboratories from Europe and, recently, from the USA have found enteroviral RNA in the tissues, including peripheral blood mononuclear cells, muscles and stomach, of patients with CFS. Chronic viral persistence through the formation of stable doublestranded RNA reconciles the two opposing observations of the past two decades: – the absence of live virions in chronically infected patients and animals and – the presence of enteroviral RNA in the blood or other tissues of patients.

Epstein-Barr virus
For many years the ubiquitous Epstein-Barr virus, present in 90% of the population, that commonly causes infectious mononucleosis also called glandular fever, was the principal suspect based on abnormal immunologic responses observed in uncontrolled studies. Subsequent studies using various types of controls have had mixed conclusions. Recent reviews consider EBV a factor either as a post infectious causal factor, or in reactivation, in subsets of patients.

Other viruses
Other implicated viruses include Ross river virus, Borna disease,  Parvovirus B19	  also herpes viruses Cytomegalovirus (HHV-5),   Human Herpesvirus Six (HHV-6) and HHV-7,    A review by Soto and Straus in 2000 states the evidence argues against an ongoing active herpes virus infection, more recent reviews suggest these viruses may play a role in triggering or perpetuating  CFS in subtypes.

Bacterial
Bacterial infections associated with CFS include;

Q Fever (Coxiella burnetii ), can cause a post infectious fatigue syndrome following infection as indicated in reveiws  and from findings. Genetic polymorphism studies support the concept of different immune states in chronic Q fever, determined by genetic variations in host immune responses.

Chlamydia pneumoniae Patients have been found in study to have higher rates of infection than controls. in review

Mycoplasma of several types and even multiple type infections have been found in high prevalence in CFS patients. One study tested persons with CFS identified in the general population and found no sign of infection. A review concludes it is not clear whether mycoplasmas are associated with CFS/FMS as causal agents, cofactors, or opportunistic infections. Although multiple bacterial and/or viral co-infections (Mycoplasma, Chlamydia, HHV-6) in CFS patients have been associated with increased severity of signs and symptoms.

Enterobacteria There have been findings of the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability associated with severity of symptoms.

Other immunological and infection findings

 * A study published in 1995 found that 3 immunological tests (protein A binding, Raji cell, or C3/C4) best discriminated CFS patients from fatigued controls.


 * A study found that while exercise worsened symptoms in CFS patients, it also increased allergen challenge response only in the CFS group, regardless of allergy status.


 * A study found that fatigue persists in a significant minority of patients for six months or more after infections, suggesting post-infective fatigue syndrome is a valid illness model for investigating CFS.


 * In a study on people who had glandular fever (which is caused by the Epstein-Barr virus), no difference was found between the levels of virus in the blood from patients who recovered quickly when compared with those whose fatigue lasted more than six months, although the latter had an altered immune response. The scientists involved believed this suggests CFS can be caused by neurological damage done (during the acute infection phase) to parts of the brain which control perception of fatigue and pain.


 * Other bacterial micro-organisms may be associated with CFS, a veterinary surgeon and his co-worker handling CFS animal cases associated with Staphylococcus spp. Bacteremia, contracted the illness and their CFS was diagnosed to CDC criteria.

Pathophysiology (2) Nervous system
Chronic fatigue is a typical symptom of neurological diseases, including chronic fatigue syndrome, is also seen in diseases that affect the central, peripheral, and autonomic nervous systems (central fatigue). Enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue. Metabolic and structural lesions can cause muscle fatigability (peripheral fatigue) also disrupt the usual process of activation in pathways interconnecting the basal ganglia (peripheral nerves), thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue. A state of low cortisol might sensitise the HPA axis to development of persistent central fatigue after stress.

Neurological abnormalities
Researchers have found evidence that CFS may involve distinct neurological abnormalities. MRI and SPECT scans show abnormalities within the brain. Studies have shown that CFS patients have abnormalities in blood flow to the brain possibly indicative of viral cause and similar but not identical compared to patients with clinical depression. A number of studies have shown that CFS patients have abnormal levels of neurotransmitters including increased serotonin (the opposite of what is found in primary depression). Reduced brain serotonin receptor sensitivity or number, and high auto antibodies to serotonin have also been found. Recent studies found altered gene expression in the brain’s serotonin and sympathetic nervous system pathways, with altered responses of the HPA axis to serotonin. Other reported neurotransmitter irregularities include glutamate, acetylcholine sensitivity associated increased cutaneous microcirculation, and autoantibodies to cholinergic receptors associated with central pain. Beta-endorphin, a natural pain killer, has been found to be low in CFS patients, the opposite of what is found in primary depression.

Dysautonomia is the disruption of the function of the autonomic nervous system (ANS). The ANS controls many aspects of homeostasis. The dysautonomia that evidences itself in CFS shows up mostly in problems of orthostatic intolerance - the inability to stand up without feeling dizzy, faint, nauseated, etc. Research into the orthostatic intolerance found in CFS indicates it is very similar to that found in postural orthostatic tachycardia syndrome (POTS) and hypocapnia. POTS and CFS patients exhibit reduced blood flows to the heart upon standing that result in reduced blood flow to the brain. The reduced blood flows to the heart are believed to originate in blood pooling in the lower body upon standing. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.
 * Dysautonomia


 * Inner-ear disorders

Problems such as Meniere's, also tumor in the inner ear, or Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness, vertigo, and fatigue. Tinnitus is also quite common. Antibodies associated with hearing loss have been found in CFS and FMS patients with inner ear disorders

Syndromes of orthostatic intolerance, in particular neurally mediated hypotension (NMH) and postural orthostatic tachycardia syndrome (POTS), have been shown to be associated with chronic fatigue syndrome. These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a tilt table test. A clinical trial of fludrocortisone, a drug sometimes used to treat low blood pressure, showed little or no benefit for people with CFS.
 * Orthostatic hypotension

Depression
There is some overlap in symptoms between depression and CFS, and sometimes cases of CFS are mistakenly attributed to clinical depression. There are, however, many clinical differences between the two.

Clinical depression often responds well to physical exercise, whereas CFS is characterised by exercise intolerance but with a willingness to be active. (See section on post-exertion symptom exacerbation.) Comorbid depression occurs in 10-15% of CFS patients and should be treated as usual, except that the patient’s energy level, cognitive dysfunction and drug sensitivity must be taken into account. Comorbid depression may be a pre-existing condition, or the result of living with CFS.

Stress and trauma
The majority of people who experience stress/trauma do not develop CFS, but these factors (including infection) increase the likelihood of acquiring CFS within one year and a genetic disposition to CFS has been demonstrated. Two studies suggest that self-reported childhood stress/trauma significantly increases the likelihood of acquiring CFS as an adult: A preliminary study found a 3 to 8 fold increase (depending on the trauma type). A study involving participants from the Swedish Twin Registry found that in matched case-control analyses, higher emotional instability and self-reported stress were significant risk factors (odds ratios, 1.72 and 1.64, respectively), while in co-twin control analyses the risk of emotional instability decreased to 1.02 whereas that of stress increased to 5.81 (suggesting genetic influences); there was also no association between extraversion and fatigue. Anxiety disorders have been associated with CFS in 5-15 year olds.

The CDC stated in 2006, their studies found gene mutation and abnormal gene activity levels in CFS patients that relate to the function of the hypothalamus-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response. Earlier CFS research also found evidence that suggested abnormal stress response was associated with subtle dysfunction of the HPA axis. Questions remain about the pathophysiology of these findings. The controversy surrounding CFS has caused some social issues for patients and may contribute to their stress (see the Social issues section).

Psychoneuroimmunological interactions
A 2006 review published in Current neurovascular research states that there is growing evidence of autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets in psychiatric disorders and hypothesizes how autoantibodies can play a role in the psychiatric disorders present in CFS. Researchers involved in a review examining an immunological basis for CFS concluded that neuropsychiatric symptoms in CFS patients may be more closely related to disordered cytokine production by glial cells within the central nervous system rather than to circulating cytokines. In one study, autoantibodies for muscarinic cholinergic receptor had been found in over half of the CFS patients and seemed to correlate with the severity of the "feeling of muscle weakness". Elevated levels of nitric oxide (not to be confused with nitrous oxide) has been found in some CFS patients. One hypothesis is that elevated levels of nitric oxide may contribute to a "sensitization" of the nervous system that results in behavioral changes.

Pathophysiology (3) Endocrine system, Other
In a 2006 update in the journal Curr Opin Psychiatry it was said; “Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered.” Alterations in serotonin signaling can lead to physiologic and behavioral changes. A 2008 study of gene polymorphisms indicates genetic predisposition possibly resulting in enhanced activity of serotonin may be involved in the pathophysiology of CFS.

Endocrine dysfunction
Thyroid and adrenal disorders can cause CFS-like symptoms, as can several other known endocrine disorders.

Hypothalamic-pituitary-adrenal axis (HPA axis)
The HPA axis controls levels of hormones such as cortisol in the body. It is activated in a circadian (daily) cycle and modulated by stress, digestion, illness and other factors, and is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body.

The HPA axis has been much studied in CFS which has shown underactivation with low cortisol not caused by adrenal insufficiency. enhanced sensitivity of the HPA axis to negative feedback, and a possibly altered diurnal cortisol rhythm. These results have not been replicated in all CFS patients, so it is not clear whether this is just a subset of patients. It is also not clear if the HPA axis abnormalities are a cause or a result of the illness. However, a review has concluded, that even if the HPA axis dysfunctions are secondary to other factors; they are a likely factor in symptom propagation in CFS.

Gene expression
Gene expression is the process by which the inheritable information in a gene, such as the DNA sequence, is made into a functional gene product, such as protein or RNA. Research into CFS has found abnormalities in gene expression, and the CDC has conducted over twenty related studies itself. It has been found that patients with CFS have specific abnormalities in expression of multiple genes which are involved in the biological process of transport (both vesicle-mediated and protein transport) and this became accentuated when CFS patients exercise. Another study found that "the differentially expressed genes imply fundamental metabolic perturbations", such as those involved in purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism. Several other studies have also suggested a genetic component to CFS involving immune dysfunction; T cell activation, perturbation of neuronal and mitochondrial function, possible links to organophosphate exposure and virus infection; immune response, apoptosis, ion channel activity, signal transduction, cell-cell signaling, regulation of cell growth and neuronal activity; some of which may be treatable with drugs that are already available. Gene expression abnormalities have been found relating to the central nervous system, metabolism and immune system; and has been associated by the CDC with impaired response to physical and psychological stresses in people with CFS. Linking genes to specific symptoms has been difficult, although is likely to be an important means to elucidate the pathogenesis of CFS. Seven subtypes of CFS/ME patients with distinct clinical differences have been identied in several gene expression studies.

Genetic polymorphisms
Polymorphism in biology occurs when two or more clearly different types exist in the same population of the same species. Preliminary studies have suggested that the risk of developing CFS may be influenced by polymorphisms in genes affecting the central nervous, endocrine,  immune,  and/or cardiovascular systems. A review published in 2007 stated that certain genetic polymorphisms might be regarded as predisposing factors.

Oxidative stress
Oxidative stress is an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. Several studies     and a review have implicated oxidative stress in CFS symptoms; especially relating to fatigue, pain and postexertional malaise/exercise intolerance. According to research, the findings on oxidative stress and nitrosative stress (nitric oxide-related toxicity); are associated with an inflammatory response, seem consistent with abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity and involves an immune response, against disrupted lipid membrane components, (by-products of lipid peroxidation ) and to nitric-oxide modified amino acids that have have become immunogenic; related to symptoms and severity in CFS. Gene expression studies suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired nerve balance strongly reflected in abnormal heart rate variability.

Metabolic disorders
Metabolic disorders and mitochondrial disorders can cause symptoms that strongly resemble CFS. Mitochondrial disturbances have been discovered in patients diagnosed with postviral fatigue syndrome. and mitochondrial dysfunction is considered a factor in PVFS and CDC defined CFS patients.

Folate deficiency (suspicion by elevated homocysteine and low serum folate) may mimic CFS symptoms.

Essential fatty acid deficiencies
Essential fatty acid levels: Several studies published between 1990 a 2005 reported finding reduced levels of Omega-6 or Omega-3 essential fatty acids in cell membranes or serum in patients diagnosed with postviral fatigue syndrome or CDC defined CFS. One study conducted in 1999 on Oxford criteria defined CFS patients (Warren et al.) found no significant differences in fatty acid levels between treatment and placebo groups. There have also been two controlled systematic proton neurospectroscopy studies of CFS patients that found raised levels of choline in brain areas consistent with an abnormality of essential fatty acid and phospholipid metabolism in the brain in CFS patients. These changes have been considered due to essential fatty acid deficiencies resulting from delta 6 desaturase (D6D) enzyme inhibition in CFS. Some researchers have suggested D6D inhibition is linked to a possible viral cause. However, researchers at an Australian University of Newcastle who reported finding, in CDC criteria defined CFS patients; a dysregulation in D6D enzyme activity and fatty acid changes consistent with an inflammatory mediated event. Found that both gradual and sudden onset had the same fatty acid anomaly differentiaiting them from controls, the primary lipid changes were potentially non-viral induced. Whilst sudden onset CFS patients could be differentiated by a key post-viral modification to fatty acids. Other studies have shown that altered ratios of fatty acids and decreased availability of omega-3 EFAs plays a role in CFS symptoms and severity and is related to findings of lowered zinc and immune dysfunction, including the lowered mitogen-stimulated activation of some T cells. The decreased cell markers are also indicators of increased inflammation and low natural killer cell activation. The reduced EFA findings are considered indicative of; oxidative stress with reduced anti-oxidant status,

Carnitine deficiency
Carnitine deficiency; is said to produce symptoms of fatigue and myalgia similar to PVFS, ME and CFS. Several studies have reported finding carnitine abnormalities in CFS patients. including lower serum total carnitine, free carnitine and acylcarnitine levels. The findings of reduced brain uptake of acetylcarnitine suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of CFS patients. There has been a contradictory study that included Oxford criteria defined patients. Others report of finding reduced levels of carnitine together with reduced essential fatty acids in patients with CDC defined CFS. Carnitine and its esters are considered to regulate the immune networks and inflammation, through carnitine-dependent; transfer of fatty acids into cells, and mitochondrial energy production from beta-oxidation of long-chain fatty acids. A gene expression study indicates altered; carnitine function, mitochondrial function, and fatty acid metabolism in PVFS. Also that profiles of plasma lipids in subgroups of CDC defined CFS patients suggest anomalies including beta-oxidation of fatty acids. As carnitine is considered an anti-oxidant, the lower plasma acetylcarnitine level may indicate, consumption by the increased oxidative stress in CFS.

Toxic agents
Insecticides have a possible effect on the cause and/or course of CFS.

Exercise findings
A large study found that higher levels of exercise in childhood is associated with a lower risk of developing CFS later on. It also found that the development of CFS was not associated with other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.

Abnormal lactic acid responses to exercise in some CFS patients,  has been suggested to be a factor in CFS because it is commonly believed to be responsible for muscle fatigue. However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.

Other findings
Other findings regarding CFS in general include:


 * Researchers compared 48 CFS patients with 29 controls and found that 10 of the CFS patients tested positive for enterovirus RNA (most closely to that of the coxsackie B virus) in their muscles while all of the 29 controls tested negative. 28 of the 48 CFS patients had an abnormal lactate response to exercise, including 9 of the 10 who tested positive for enterovirus RNA.


 * Researchers have found that children and teenagers with CFS are several times more likely to have some hyperflexible joints in an association with Ehlers-Danlos syndrome.