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.
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.
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.
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.
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.
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.
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.
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.
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.