The pathogenesis of chronic fatigue syndrome (CFS) is uncertain, but may involve multiple organ and body systems, including neurological, endocrinal and immunological factors.

Nervous system factors

Neurological abnormalities

CFS may involve neurological abnormalities, revealed by MRI and SPECT scans, blood flow measurements, studies of the serotonin signalling pathways, and gene expression. Levels of beta-endorphin, a natural pain killer, are low in some CFS patients. Some of these findings resemble viral infection and clinical depression, while others do not.

Dysautonomia is the disruption of the function of the autonomic nervous system (ANS) which controls many aspects of homeostasis. In CFS this is mostly orthostatic intolerance - the inability to stand up without feeling dizzy, faint, or nauseated. Research on CFS orthostatic intolerance shows associations with nerually mediated hypotension and postural orthostatic tachycardia syndrome, as well as hypocapnia. These conditions may cause blood to pool in the lower body when a person stands, reducing blood flow to the heart and brain. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.

Depression and other psychiatric disorders

CFS symptoms are often attributed to clinical depression; there are clinical overlaps and differences between the two. Depression occurs in 10-15% of CFS patients. Previous psychiatric disorders or shared risk factors for psychiatric disorders may have an etiological role in some cases of CFS. The presence of multiple comorbid disorders could be a marker for psychological influences on etiology. Neuropsychological impairments could be involved in CFS, and neuroendocrine studies and brain imaging have confirmed the occurrence of neurobiological abnormalities in most patients with CFS.

Findings of increased autoimmune antibodies against phosholipids (phosphatidyl inositol) in CFS and depression may underpin the similarities and comorbity between the two disorders. Psychosocial Central sensitization could be responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images. Behavioral High levels of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS. It has been hypothesized that in CFS the health threat is no longer the illness, but rather anything that threatens to disrupt a precarious accommodation to it. Due to established vicious circles, attempts at threat regulation may become inadvertently self-defeating, promoting the threats they attempt to diminish. In one study, CFS patients were found to have consulted their GP more frequently in the 15 years before development of their condition, for a wide variety of complaints, supporting a hypothesis that behavioural factors might have a role in the etiology of CFS.

Stress and trauma

The majority of people who experience stress or trauma do not develop CFS, but these factors may increase the likelihood of acquiring CFS. Self-reported childhood stress or trauma increases the likelihood of acquiring CFS as an adult. A study of twins found both stress and genetics could contribute to CFS, and anxiety disorders have been associated with CFS in 5-15 year olds. CDC studies found gene mutation and abnormal gene activity levels in CFS patients that may relate to the function of the hypothalamus-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response.

Psychoneuroimmunological interactions

The brain and immune system influence each other, especially in the HPA axis and sympathetic nervous system. Mental stress causes suppression of the immune system by hormones such as cortisol and epinepherine. Release of stress hormones, caused by diseases outside the brain, can result in neurological symptoms due to the influence of stress hormones on neurotransmitters. Neuropsychiatric disorders present in CFS may be related to autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets, or disordered cytokine production by glial cells within the central nervous system.

Infections

Viral and bacterial infections have been associated with CFS but their influence on etiology and pathophysiology is controversial. Some researchers say there is a higher winter onset of CFS, and their hypothesis is that symptom onset is precipitated by a viral infection in some people. Other experts say while symptoms of CFS can occur after severe infection, no convincing data exist to support an infectious process in disease maintenance.

Enteroviruses like the Coxsackie virus and Polio virus have been associated with symptoms resembling CFS. The validity and implications of enterovirus findings are controversial. Epstein-Barr virus (EBV) is present in 90% of the general population and sometimes causes infectious mononucleosis (glandular fever). EBV was once the principal suspect in chronic fatigue illnesses, but mixed study results have led to the current view of EBV in some patients as either a post infectious causal factor or a factor in reactivation. Other viruses implicated by some researchers include Ross river virus, Borna disease, Parvovirus B19, and herpes viruses Cytomegalovirus (HHV-5), Human Herpesvirus Six (HHV-6), and HHV-7. A role for herpes viruses in CFS is controversial.

Several bacteria have been associated with some cases of CFS. Q Fever, caused by Coxiella burnetii, can cause a post infectious fatigue syndrome resembling CFS CFS patients reportedly have higher rates of Chlamydia pneumoniae infection than controls. The possible influence of Mycoplasma is disputed, with reports for and against. A review concludes the role of Mycoplasma as causal agents, cofactors, or opportunistic infections is not clear. Gram-negative enterobacteria and increased intestinal permeability may be associated with severity of CFS symptoms. Multiple bacterial and/or viral co-infections (Mycoplasma, Chlamydia, HHV-6) have been associated with increased severity of signs and symptoms.

Immunological dysfunction

Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS, but they may not represent the entire picture and some CFS experts doubt they are responsible.

Autoimmune disorders and allergies or food intolerance have been reported in CFS sufferers. Gene expression changes have been reported in the white blood cells of CFS patients, consistent with the theory of immune system activation, and abnormal types of antiviral protein RNase L are postulated to affect sleep-wake cycles and exercise capacity. High levels of Th2-type cytokines and the cells that make them are also found in CFS. The resulting, increased antibody production may explain some immune dysfunctions in CFS. A reduction in the opposite Th1 response has also been reported, with implications for altered Th1/Th2 balance. Therapeutic alterations of cytokine expression patterns are being investigated.

In contrast, immunodeficiency disorders characterized by abnormal T-cell subset ratios, levels of immunoglobulins, and hypoallergic responses on the French Multitest have been reported in CFS. Patients with lower natural killer cell activity report less vigor, more daytime dysfunction, and more cognitive impairment 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).

Altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and neurological symptoms found in CFS. The monocyte /macrophage, which crosses the blood brain barrier, is an essential candidate cell in the study of psychoneuroimmunology.

Endocrine system

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. Polymorphisms in genes related to serotonin pathways may indicate genetic predisposition in the pathophysiology of CFS. Some researchers think cold therapy can increase serotonin levels to treat CFS.

Thyroid and adrenal disorders can cause CFS-like symptoms, as can several other known endocrine disorders. The hypothalamic-pituitary-adrenal axis (HPA axis) controls levels of hormones such as cortisol and is activated in a circadian rhythms and modulated by factors such as stress, digestion or illness. It is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body. In CFS there is seen low cortisol, enhanced sensitivity of the HPA axis to negative feedback, and a possibly altered diurnal cortisol rhythm. These results may not apply in all CFS, and the HPA axis abnormalities could be a cause or a result. Some researchers say they are a likely factor in symptom propagation in CFS.

Gene expression and polymorphisms

CFS-related abnormalities in gene expression have been studied, including by the CDC. Changes in genes involved in transport (both vesicle-mediated and protein transport), metabolism, immune regulation, neuronal function, mitochondrial function, apoptosis, and other processes have been reported. The CDC has said these changes could be involved in CFS. Some of the symptoms of gene expression differences may be treatable with existing drugs. Some researchers think gene expression studies could make possible better categorization of CFS and even help with differential diagnosis.

Some researchers think genetic polymorphisms are predisposing factors for CFS. Polymorphism in biology occurs when two or more clearly different types exist in the same population of the same species. The risk of developing CFS may also be influenced by these small genetic differences in genes of 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.

Other hypotheses

Oxidative stress

Oxidative stress, 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 is consistant with CFS symptoms, especially relating to fatigue, pain and exercise intolerance. Gene expression studies suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired nerve balance, reflected in abnormal heart rate variability.

Hypothesis of CFS in which either viral or bacterial infection induces one or more cytokines. These induce nitric oxide synthase (iNOS), leading to increased nitric oxide levels. Nitric oxide, in turn, reacts with superoxide radical to generate the potent oxidant peroxynitrite. Multiple amplification and positive feedback mechanisms are proposed by which once peroxynitrite levels are elevated, they tend to be sustained at a high level. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS, FMS and MCS. Stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO- cycle that is responsible for symptoms in chronic illness. The role of peroxynitrite in the NO/ONOO- cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment.

The role of oxidative stress in CFS is an emerging focus of research due to evidence of its association with some pathological features of this syndrome. New data collectively supports the presence of specific critical points in the muscle membranes that are affected by free radicals and in view of these considerations, the possible role of skeletal muscle oxidative imbalance in CFS is considered. The oxidative stress induced muscle membrane modifications may be related to alteration of membrane fluidity with deregulation of pump activities, sodium / potassium (Na(+)/K(+) and calcium (Ca(2+)-ATPase).

Selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in CFS pathogenesis. The results of a study indicate that patients with CFS have increased susceptibility to peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

Evidence is put forward to suggest that myalgic encephalomyelitis, also known as chronic fatigue syndrome, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesise n-3 and n-6 long-chain polyunsaturated fatty acids by inhibiting the delta-6 desaturation of the precursor essential fatty acids--namely, alpha-linolenic acid and linoleic acid. This would, in turn, impair the proper functioning of cell membranes. Alternatively oxidative stress might reduce essential fatty acids in membranes of chronic fatigue syndrome patients.

Several papers explain that depletion of essential fatty acids can result from an immune hyper-response, mediated either by immuno-globulins, by sustained cytokines, and/or by reduced lipo-cortin control (due to HPA hypo function) or by excessive metabolic mobilization of essential fatty acids. Oxygenases are suppressed in normal tissues but are activated by lipid hydroperoxides. Hydroperoxides are needed as activators to sustain production but one immediate product of fatty acid oxygenase action is lipid hydroperoxide. Positive feeback amplifies the peroxide in vicinity to the oxygenase, leading to free radical generation, oxidative stress and substrate depletion; the result of sustained extracellular signalling and intracellular amplification.

Hypothesis that changes in ratio of essential fatty acid metabolites are the normal physiological responses to stressors, but when stressors are excessive or prolonged, systems may become unpredictably hypo-responsive after sustained hyper responses owing to factors such as receptor down regulation and substrate depletion. In time, many homeostatic systems become deranged and vicious circles held in that state by minor stressors.

The inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) have been found raised in CFS patients associated with symptoms and provides evidence to support hypotheses that CFS is accompanied by increased oxidative stress and inflammation.

Metabolic disorders

Metabolic disorders and mitochondrial disorders can cause symptoms that resemble CFS. Mitochondrial disturbances have been discovered in patients diagnosed with postviral fatigue syndrome. Folate deficiency may also 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 may produce symptoms of fatigue and myalgia, and low serum total carnitine, free carnitine and acylcarnitine levels have been reported in CFS. Biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of CFS patients. Others report of finding reduced levels of carnitine together with reduced essential fatty acids in patients with CDC defined CFS. A gene expression study indicates altered carnitine function, mitochondrial function, and fatty acid metabolism in post-infective fatigue.

Toxic agents

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

Exercise findings

Childhood exercise and adult risk of CFS are inversely correlated in a large study finding 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 have 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

Children and teenagers with CFS are several times more likely than healthy controls to have some hyperflexible joints in an association with Ehlers-Danlos syndrome.

References