Pathophysiology of chronic fatigue syndrome

The pathophysiology of chronic fatigue syndrome is unknown. Several potential causes for the development of chronic fatigue syndrome have been proposed, including neurological factors, psychological or psychosocial factors or influences, infections, immunological factors, endocrinal factors and genetic factors. Other, less-common theories have also been articulated. No clinically meaningful risk factor has been identified.[1]

Nervous system factors

Neurological abnormalities

CFS may involve neurological abnormalities, revealed by MRI and SPECT scans,[2] blood flow measurements,[3] studies of the serotonin signalling pathways,[4][5] and gene expression.[6] Levels of beta-endorphin, a natural pain killer, are low in some CFS patients.[7] Some of these findings resemble viral infection[8] and clinical depression, while others do not.[9]

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.[10] Research on CFS orthostatic intolerance shows associations with neurally mediated hypotension and postural orthostatic tachycardia syndrome,[11][12][13] as well as hypocapnia.[14] 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.[15][16]

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,[17][18] or disordered cytokine production by glial cells within the central nervous system.[19]

Psychological and psychosocial

The possible involvement of psychological factors within CFS is both unclear and contentious,[20][21] with several psychological and psychosocial factors having been theorized. Some individuals with CFS firmly reject any psychological involvement and believe strongly that their condition has a physical cause.[22]

Behavioral

High levels of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS.[23][24] 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.[25]

Neuroticism and introversion have previously been reported as risk factors for developing CFS.[26] A recent systematic review of personality and CFS found an association with neuroticism, but stated that it was often accounted for by co-morbid depression and levels were similar to those in patients with other chronic diseases, and found no firm evidence for introversion.[27]

Cognitive behavioural model

According to the cognitive-behavioural model of illness, the patient's interpretation of symptoms plays an important role in perpetuating the illness. Catastrophic interpretations of symptoms, the belief that symptoms are beyond the patient's control and excessive emotional reactions may accentuate the physiological changes giving rise to symptoms. The cognitive-behavioural model differs from the extreme psychological model which proposes that illness symptoms are exclusively mental.[28] In response to a version of the cognitive behavioural model described in the book "Chronic Fatigue and Its Syndromes", the authors of a status report on CFS state, "Although this model may explain continued illness in some CFS patients, it certainly does not pertain to all CFS patients and is thus not too satisfactory."[29]

Fixation

Some research suggests that CFS may be perpetuated when patients fixate on a physical cause for their symptoms or when exercise is avoided.[26][30]

Illness behavior

A lack of support, or the reinforcement of illness behavior by social networks, may be associated with delayed recovery for some patients.[26]

Mood disorders

There are clinical overlaps and differences between CFS and clinical depression. Current mood disorders occur in 18.9% of CFS patients compared to 3.9% of the general population.[31] Previous psychiatric disorders or shared risk factors for psychiatric disorders may have an etiological role in some cases of CFS.[32] The presence of multiple comorbid disorders could be a marker for psychological influences on etiology.[33] Neuropsychological impairments could be involved in CFS,[34] and neuroendocrine studies and brain imaging have confirmed the occurrence of neurobiological abnormalities in most patients with CFS.[35] Findings of increased autoimmune antibodies against phospholipids (phosphatidyl inositol) in CFS and depression may underpin the similarities and comorbity between the two disorders.[36]

Sensitization

Central sensitization could be responsible for the sustaining pain complaints in CFS. Elevated concentrations of nitric oxide are present in the blood of CFS patients, and brain imaging shows brain abnormalities. Catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by, sensitization of the central nervous system.[37]

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.[38][39][40] A systematic scoping review included one retrospective study which reported that childhood trauma was significantly associated with the development of adult CFS, one prospective study which reported that genetics and self-reported stress sensitivity could contribute to CFS-like illness 25 years later, and one prospective study on fatigued employees which took measurements of current psychological distress and recent "shocking life events" (within last 12 months) at baseline and 12/24 month followup but did not find these to predict CFS-like caseness at 44 month followup.[1] Anxiety disorders may be associated with CFS in 5- to 15-year-olds.[41] CDC studies found gene mutation and abnormal gene activity levels in CFS patients that may relate to the function of the hypothalamic-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response.[42]

Infections

Many viral and bacterial infections have been proposed to cause or associate with CFS, but no infectious influence on pathophysiology has been proven. A reportedly higher winter onset of CFS has led some to hypothesise that symptom onset is precipitated by a viral infection in some people.[43][44] However, although symptoms of CFS can occur after severe infection, strong data do not yet exist to support an infectious process in disease maintenance.[29]

Bacteria

Q Fever, caused by Coxiella burnetii, can cause a post infectious fatigue syndrome resembling CFS.[45][46][47] CFS patients reportedly have higher rates of Chlamydia pneumoniae infection than controls.[45][48] The possible influence of mycoplasma is disputed, with reports for[49][50][51][52] and against.[53] A review concludes the role of mycoplasma as causal agents, cofactors, or opportunistic infections is not clear.[54] Gram-negative enterobacteria and increased intestinal permeability may be associated with severity of CFS symptoms.[55] Associations of multiple bacterial and/or viral co-infections (mycoplasma, Chlamydia, HHV-6) with increased severity of signs and symptoms have also been proposed.[48]

Viruses

Enteroviruses like the Coxsackie virus[56] and Polio virus have been associated with symptoms resembling CFS. A number of studies have investigated enterovirus infections in CFS patients, but the results are contradictory and no causal relationship has been demonstrated.[57] 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,[58][59] but mixed study results[60][61][62] have led to the current view of EBV in some patients as either a post infectious causal factor[45][63] or a factor in reactivation.[64] Other viruses implicated by some researchers include Ross river virus;[65] Borna disease;[66] Parvovirus B19;[45] and herpes viruses Cytomegalovirus (HHV-5),[67] Human Herpesvirus Six (HHV-6), and HHV-7.[68][69] A role for herpes viruses in CFS is controversial.[70][71]

In 1991, retrovirus sequences similar to human T-lymphotropic virus (HTLV) type II were reportedly found in the blood of a subset of CFS patients and not in healthy controls.[72] This finding was not replicated, and no evidence of infection with human retroviruses was found.[72]

In 2009, another retrovirus, xenotropic murine leukemia virus-related virus (XMRV), was reportedly detected in the blood of 67% of CFS patients but in only 3.7% of healthy controls by a team led by Judy Mikovits of the Whittemore Peterson Institute.[73] Follow-up studies detected no XMRV in CFS patients, patients with other conditions, or healthy controls in experiments using one or more methods including polymerase chain reaction, antibody-based detection and viral culture.[74][75][76][77][78][79][80][81][82] Several studies indicated that contamination contributed to the initial XMRV positive findings.[82][83][84][85][86][87][88][89][90][91][83] A study with samples from the patient group used in the only positive study found no XMRV, but reported that reagents used by the Mikovits group contained mouse DNA contamination.[82] These reagents were also used by another group that found mouse viruses (but not XMRV) in CFS samples.[92] The authors stated, however, that this contamination did not explain the striking differences between disease and control samples in the initial report, and stressed the importance of blinding samples to avoid introduction of inadvertent bias.[82] The editors of Science, in which the 2009 report was published, have attached an "Editorial Expression of Concern" to the report indicating that the validity of the study "is now seriously in question".[93] In September 2011, the original authors published a "Partial Retraction" of their 2009 findings, in which they acknowledged that "some of the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA."[94]

In December 2011, Science and Proceedings of the National Academy of Science, withdrew published papers claiming sufferers carried the virus. Don Staines, from ME/CFS Australia says, "That area of research is pretty well dead and buried".[95][96][97]

Immunological dysfunction

Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS,[98] but they may not represent the entire picture[99] and some CFS experts doubt they are responsible.[29] A 2003 review concluded that "no consistent pattern of immunological abnormalities is identified" in CFS.[100] A 2009 review into the immunological aspects of CFS reported that patients do seem to have a specific immune dysfunction profile involving an enhanced baseline activation of lymphoid subsets but a suppression of certain immune responses, particularly Th1-driven ones such as the anti-viral and anti-tumour responses. Reported findings from various studies include an alteration in cytokine profile (high level of pro-inflammatory cytokines and dysregulation of anti-inflammatory cytokines), decreased function of natural killer (NK) cells, the presence of autoantibodies, reduced responses of T cells and abnormal activation of T lymphocyte subsets. The authors note that the immune alteration pattern of CFS "has a striking resemblance to the one caused by developmental immune toxicology", perhaps due to a combination of factors such as xenobiotics, infections and stress.[101]

Allergies or food intolerance[102] have been reported in CFS sufferers. Gene expression changes have been reported in the white blood cells of CFS patients. This is consistent with the theory of abnormal types of antiviral protein RNase L and are postulated to affect sleep-wake cycles and exercise capacity.[103] High levels of Th2-type cytokines and the cells that make them are also found in CFS.[98][104][105][106] Therapeutic alterations of cytokine expression patterns are being investigated.[104][107]

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.[104]

HPA axis

The hypothalamic-pituitary-adrenal axis (HPA axis) controls levels of hormones such as cortisol and is activated in a circadian rhythm 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.

A substantial body of evidence points to the following findings in CFS patients: mild hypocortisolism, an attenuated diurnal variation in cortisol, enhanced cortisol negative feedback, and a blunted HPA axis responsiveness. Women are more likely to exhibit hypocortisolism than men, as well as those who are depressed, inactive or not taking medication. The findings are similar to those seen in atypical depression. Glucocorticoid and mineralocorticoid receptor hypersensitivity appears to be the most probable explanation for the enhanced HPA axis negative feedback. Patients who undergo treatment such as CBT show reversal of the HPA axis changes. Steroid replacement therapy is not recommended due to lack of evidence and possible adverse effects.[108]

It has been debated whether these disturbances would play a primary role in the pathogenesis of CFS, but prospective evidence suggests that the HPA axis is not an important factor during the early stages of CFS, although it has been hypothesized that it might play a role in exacerbating or perpetuating symptoms later on in the course of the illness.[109][110][111] A 2011 meta-analysis reported a small but statistically significant hypocortisolism in CFS.[112] A study of cognitive behavioural therapy for CFS, which also measured cortisol levels, had observed that hypocortisolism was associated with a poorer response to CBT.[113]

A 2006 update in the journal Current Opinion in Psychiatry stated, "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."[99]

Serotonin signaling

Hyperactivity of the serotonergic system has been implicated in CFS. 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.[114]

Gene expression and polymorphisms

CFS-related abnormalities in gene expression have been studied.[42][115] Changes in genes involved in transport (both vesicle-mediated and protein transport),[116] metabolism,[117] immune regulation, neuronal function, mitochondrial function, apoptosis and other processes have been reported.[118][119][120] The CDC has said these changes could be involved in CFS.[42] Some of the symptoms of gene expression differences may be treatable with existing drugs.[121] Some researchers think gene expression studies could make possible better categorization of CFS[122][123] and even help with differential diagnosis.[124]

An abnormally large and rapid mRNA activation of sensory, immune/cytokine and adrenergic receptors have been implicated in the post-exertional symptoms experienced by CFS patients after exercise.[125]

A 2007 review stated that certain genetic polymorphisms might be regarded as predisposing factors.[126] Studies have shown genetic differences in genes of CFS patients and healthy controls in the central nervous,[114][127] endocrine,[6][128][129] immune [130][131] and cardiovascular systems.[132]

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, occurs in CFS and helps to explain the muscle pain, postexertional malaise, and the decrease in pain threshold following graded exercise.[133] 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.[134]

Metabolic disorders

Metabolic disorders and mitochondrial disorders can cause symptoms that resemble CFS.[135] Mitochondrial disturbances have been discovered in patients diagnosed with post-viral fatigue syndrome.[136] Folate deficiency may also mimic CFS symptoms.[137][138]

Essential fatty acid deficiencies

Essential fatty acid levels: Several studies published between 1990 and 2005 reported finding reduced levels of Omega-6 or Omega-3 essential fatty acids in cell membranes or serum in patients diagnosed with post-viral fatigue syndrome or CDC-defined CFS.[139][140][141][142] 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.[143] A review of CFS treatments compared two studies of essential fatty acids, concluding that there is insufficient evidence to recommend it as a treatment for CFS.[144]

Toxic agents

Insecticides have a possible effect on the cause and/or course of CFS.[45] Chronic exposure to organophosphates, a pesticide, has neurophsychiatric effects including cognitive impairment and chronic fatigue,[145] and according to a paper by Davies, the CDC includes organophosphates as a cause of (CFS). The authors, however, state that a diagnosis of CFS may be unhelpful and misleading in people with organophosphate toxicity.[146]

Exercise findings

In a large national birth cohort study, the risk of developing CFS as an adult was inversely correlated with childhood exercise, but no association was found for other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.[147] However, a similar study found that an increased level of exercise in childhood and early-adulthood is a risk factor.[148]

Abnormal lactic acid responses to exercise in some CFS patients[149][150][151] have been suggested to be a factor in CFS because it is commonly believed to be responsible for muscle fatigue.[152] 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.[153]

Other findings

Children and teenagers with CFS are several times more likely than healthy controls to have some hyperflexible joints[154] in an association with Ehlers-Danlos syndrome.

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