Tag: review

Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O&NS-mediated damage to fatty acids, DNA and proteins, autoimmune reactions directed against neoantigens and brain disorders. Mitochondrial dysfunctions have been found in ME/cfs, e.g. lowered ATP production, impaired oxidative phosphorylation and mitochondrial damage.

This paper reviews the pathways that may explain mitochondrial dysfunctions in ME/cfs. Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ω3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways.

Therefore, it may be concluded that immuno-inflammatory and O&NS pathways may play a role in the mitochondrial dysfunctions and consequently the bioenergetic abnormalities seen in patients with ME/cfs. Defects in ATP production and the electron transport complex, in turn, are associated with an elevated production of superoxide and hydrogen peroxide in mitochondria creating adaptive and synergistic damage.

It is argued that mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/cfs symptoms, e.g. fatigue and post exertional malaise, and may explain in part the central metabolic abnormalities observed in ME/cfs, e.g. glucose hypometabolism and cerebral hypoperfusion.

 

Source: Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014 Mar;29(1):19-36. doi: 10.1007/s11011-013-9435-x. Epub 2013 Sep 10.https://www.ncbi.nlm.nih.gov/pubmed/24557875

 

Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review

Abstract:

OBJECTIVE: To identify case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and explore how the validity of case definitions can be evaluated in the absence of a reference standard.

DESIGN: Systematic review.

SETTING: International.

PARTICIPANTS: A literature search, updated as of November 2013, led to the identification of 20 case definitions and inclusion of 38 validation studies.

PRIMARY AND SECONDARY OUTCOME MEASURE: Validation studies were assessed for risk of bias and categorised according to three validation models: (1) independent application of several case definitions on the same population, (2) sequential application of different case definitions on patients diagnosed with CFS/ME with one set of diagnostic criteria or (3) comparison of prevalence estimates from different case definitions applied on different populations.

RESULTS: A total of 38 studies contributed data of sufficient quality and consistency for evaluation of validity, with CDC-1994/Fukuda as the most frequently applied case definition. No study rigorously assessed the reproducibility or feasibility of case definitions. Validation studies were small with methodological weaknesses and inconsistent results. No empirical data indicated that any case definition specifically identified patients with a neuroimmunological condition.

CONCLUSIONS: Classification of patients according to severity and symptom patterns, aiming to predict prognosis or effectiveness of therapy, seems useful. Development of further case definitions of CFS/ME should be given a low priority. Consistency in research can be achieved by applying diagnostic criteria that have been subjected to systematic evaluation.

 

Source: Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 2014 Feb 7;4(2):e003973. doi: 10.1136/bmjopen-2013-003973. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918975/ (Full article)

 

Chronic fatigue syndrome: a personalized integrative medicine approach

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a relatively common illness, yet despite considerable investigation, current treatments have modest benefits, and the prognosis remains poor. Because CFS/ME is a heterogeneous disorder with diverse etiological factors and pathological features, a patient-centered integrative framework based on modifiable physiological and environmental factors may offer hope for more effective management and better clinical outcomes. An individualized approach may also help target interventions for subgroups most likely to respond to specific treatments. This review summarizes a number of avenues for integrative management, including dietary modification, functional nutritional deficiencies, physical fitness, psychological and physical stress, environmental toxicity, gastrointestinal disturbances, immunological aberrations, inflammation, oxidative stress, and mitochondrial dysfunction. A personalized, integrative approach to CFS/ME deserves further consideration as a template for patient management and future research.

 

Source: Brown B. Chronic fatigue syndrome: a personalized integrative medicine approach. Altern Ther Health Med. 2014 Jan-Feb;20(1):29-40. https://www.ncbi.nlm.nih.gov/pubmed/24445354

 

Chronic Fatigue Syndrome: Case Definitions and Diagnostic Assessment

Abstract:

Chronic fatigue syndrome (CFS) is a chronic, debilitating illness that has posed considerable challenges for both patients and health care providers. Individuals with CFS often deal with considerable stigma and difficulties accessing appropriate care. Many medical professionals are increasingly recognizing the devastating nature of this illness, but at this time, few health care workers are knowledgeable and experienced enough to provide adequate patient care. There is a need for further efforts to educate health care workers on CFS diagnostic, assessment, and treatment issues. The present article reviews controversies regarding CFS case definitions, diagnostic criteria, the name of the illness, and epidemiological and treatment studies. We conclude that an imprecise case definition underlies many of the problems with diagnostic and treatment issues.

 

Source: Williams YJ, Jantke RL, Jason LA. Chronic Fatigue Syndrome: Case Definitions and Diagnostic Assessment. N Y State Psychol. 2014 Winter;26(4):41-45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008849/ (Full article)

 

Natural killer cells in patients with severe chronic fatigue syndrome

Abstract:

Maintenance of health and physiological homeostasis is a synergistic process involving tight regulation of proteins, transcription factors and other molecular processes. The immune system consists of innate and adaptive immune cells that are required to sustain immunity. The presence of pathogens and tumour cells activates innate immune cells, in particular Natural Killer (NK) cells.

Stochastic expression of NK receptors activates either inhibitory or activating signals and results in cytokine production and activation of pathways that result in apoptosis of target cells. Thus, NK cells are a necessary component of the immunological process and aberrations in their functional processes, including equivocal levels of NK cells and cytotoxic activity pre-empts recurrent viral infections, autoimmune diseases and altered inflammatory responses. NK cells are implicated in a number of diseases including chronic fatigue syndrome (CFS). The purpose of this review is to highlight the different profiles of NK cells reported in CFS patients and to determine the extent of NK immune dysfunction in subtypes of CFS patients based on severity in symptoms.

 

Source: Brenu EW, Hardcastle SL, Atkinson GM, van Driel ML, Kreijkamp-Kaspers S, Ashton KJ, Staines DR, Marshall-Gradisnik SM. Natural killer cells in patients with severe chronic fatigue syndrome. Auto Immun Highlights. 2013 Apr 16;4(3):69-80. doi: 10.1007/s13317-013-0051-x. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389023/ (Full article)

 

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

Abstract:

BACKGROUND: ‘Encephalomyelitis disseminata’ (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS.

DISCUSSION: There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses.

Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses.

Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.

SUMMARY: This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.

 

Source: Morris G, Maes M. Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Med. 2013 Sep 17;11:205. doi: 10.1186/1741-7015-11-205. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847236/ (Full article)

 

The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs)

Abstract:

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses.

A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies.

The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

 

Source: Morris G, Berk M, Galecki P, Maes M. The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol Neurobiol. 2014 Apr;49(2):741-56. doi: 10.1007/s12035-013-8553-0. Epub 2013 Sep 26. https://www.ncbi.nlm.nih.gov/pubmed/24068616 (Full article)

 

Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome

Abstract:

OBJECTIVE: Somatization is a symptom cluster characterized by ‘psychosomatic’ symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of ‘psychosomatic’ symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms.

METHOD: This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI).

RESULTS: The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc.

CONCLUSION: Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comment in

Source: Anderson G, Berk M, Maes M. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome. Acta Psychiatr Scand. 2014 Feb;129(2):83-97. doi: 10.1111/acps.12182. Epub 2013 Aug 17. https://www.ncbi.nlm.nih.gov/pubmed/23952563

 

Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis

Abstract:

The hypothalamic-pituitary-adrenal (HPA) axis is a psychoneuroendocrine regulator of the stress response and immune system, and dysfunctions have been associated with outcomes in several physical health conditions. Its end product, cortisol, is relevant to fatigue due to its role in energy metabolism.

The systematic review examined the relationship between different markers of unstimulated salivary cortisol activity in everyday life in chronic fatigue syndrome (CFS) and fatigue assessed in other clinical and general populations. Search terms for the review related to salivary cortisol assessments, everyday life contexts, and fatigue. All eligible studies (n=19) were reviewed narratively in terms of associations between fatigue and assessed cortisol markers, including the cortisol awakening response (CAR), circadian profile (CP) output, and diurnal cortisol slope (DCS).

Subset meta-analyses were conducted of case-control CFS studies examining group differences in three cortisol outcomes: CAR output; CAR increase; and CP output. Meta-analyses revealed an attenuation of the CAR increase within CFS compared to controls (d=-.34) but no statistically significant differences between groups for other markers. In the narrative review, total cortisol output (CAR or CP) was rarely associated with fatigue in any population; CAR increase and DCS were most relevant.

Outcomes reflecting within-day change in cortisol levels (CAR increase; DCS) may be the most relevant to fatigue experience, and future research in this area should report at least one such marker. Results should be considered with caution due to heterogeneity in one meta-analysis and the small number of studies.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

 

Source: Powell DJ, Liossi C, Moss-Morris R, Schlotz W. Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis. Psychoneuroendocrinology. 2013 Nov;38(11):2405-22. doi: 10.1016/j.psyneuen.2013.07.004. Epub 2013 Aug 2. http://www.psyneuen-journal.com/article/S0306-4530(13)00254-0/fulltext (Full article)

 

Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review

Abstract:

OBJECTIVE: The goal of this systematic literature review is to determine whether there are differences and similarities in heart rate variability (HRV) between adult patients with fibromyalgia

(FM), chronic fatigue syndrome (CFS), and healthy pain-free control subjects.

METHODS: To obtain relevant articles, PubMed and Web of Knowledge were searched for case-control studies. Selection of the literature was based on selection criteria ascertaining studies with adult human patient groups comparing HRV. Risk of bias and levels of evidence were determined.

RESULTS: Sixteen case-control studies were included, 10 comparing FM patients to controls and 6 comparing CFS patients to controls. Methodological quality was moderate to good. Both time domain and frequency domain measurements were used. The majority of the researchers observed lower HRV in FM patients compared to healthy control persons, as well as increased sympathetic activity and a blunted autonomic response to stressors. Resistance training improved HRV in FM patients. In CFS patients HRV was only reduced during sleep.

CONCLUSION: FM patients show more HRV aberrances and indices of increased sympathetic activity. Increased sympathetic activity is only present in CFS patients at night. Since direct comparisons are lacking and some confounders have to be taken into account, further research is warranted. The role of pain and causality can be subject of further research, as well as therapy studies directed to reduced HRV.

© 2013 Elsevier Inc. All rights reserved.

Comment in

Source: Meeus M, Goubert D, De Backer F, Struyf F, Hermans L, Coppieters I, De Wandele I, Da Silva H, Calders P. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review. Semin Arthritis Rheum. 2013 Oct;43(2):279-87. doi: 10.1016/j.semarthrit.2013.03.004. Epub 2013 Jul 6. https://www.ncbi.nlm.nih.gov/pubmed/23838093