Pathophysiology – Page 32 – American ME and CFS Society

Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study

Abstract:

AIM: since patients with chronic fatigue syndrome (CFS) often present elevated levels of nitric oxide (NO) and low levels of physical activity, this study aimed at revealing possible correlations between NO concentration and physical activity.

PATIENTS AND METHODS: thirty CFS patients and 29 age- and gender-matched sedentary controls wore an accelerometer for one week and underwent venous blood sampling at the beginning and the end of the week.

RESULTS: CFS patients were significantly less active (p=0.001), but no significant differences in the amounts of NO (p=0.464 and 0.569) or interaction between NO levels and activity levels in either the CFS patients or controls were revealed.

CONCLUSION: these results provide further evidence for reduced activity levels in CFS patients, but refute there being any interaction between the amount of blood NO and activity level in both groups. The blood NO was neither predictive of, nor dependent on the activity level in CFS.

Source: Meeus M, VAN Eupen I, Hondequin J, DE Hauwere L, Kos D, Nijs J. Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study. In Vivo. 2010 Nov-Dec;24(6):865-9. https://www.ncbi.nlm.nih.gov/pubmed/21164046

Lipid peroxidation is elevated in female patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome is a debilitating disease of unclear cause and pathogenesis. It affects mostly women from lower socioeconomic classes. There is mounting evidence that oxidative stress, specifically lipid peroxidation (LPO) contributes to the disease process. We investigated levels of LPO and its possible consequences for these patients.

MATERIAL/METHODS: Forty women aged 15-45 years who fulfilled the 1994 Centers for Disease Control’s diagnostic criteria for chronic fatigue syndrome (CFS) with no comorbidities were recruited and were age matched to a control group of 40 healthy women. Levels of total cholesterol (TC), triglycerides (TG), LDL cholesterol (LDLc), HDL cholesterol (HDLc), and malondialdehyde (MDA) levels were measured.

RESULTS: Although initial statistical analyses showed no differences between groups (P=.345), when subdivided according to the level of MDA, a difference was found in the subgroup of high-level MDA (P=.034). There was a negative correlation between HDLc and MDA levels (r=0.3; P=.046), a positive correlation between TG and MDA levels (r=0.4; P=.006), and lower levels of HDL cholesterol in the CFS group (P=.036).

CONCLUSIONS: High levels of MDA, positively correlated with TG and lower HDL levels, might be indicative of proatherogenic events in female CFS patients, a group not otherwise considered a risk for atherosclerosis.

Source: Brkic S, Tomic S, Maric D, Novakov Mikic A, Turkulov V. Lipid peroxidation is elevated in female patients with chronic fatigue syndrome. Med Sci Monit. 2010 Dec;16(12):CR628-32. https://www.ncbi.nlm.nih.gov/pubmed/21119582

Gynecological history in chronic fatigue syndrome: a population-based case-control study

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) affects disproportionately more women than men, and the condition is more common at perimenopause. We examined gynecological history events as risk factors for CFS.

METHODS: In a case-control study from a randomly selected population sample from Wichita, Kansas, 36 women with CFS and 48 nonfatigued controls, of similar age, race, and body mass index (BMI), answered a structured gynecological history questionnaire.

RESULTS: CFS cases and controls had the same mean age (51 years) and age at menarche (12 years). Overall, a greater proportion of women with CFS than controls reported pelvic pain unrelated to menstruation (22.2% vs. 1.7%, p = 0.004), endometriosis (36.1% vs. 16.7, %, p = 0.046), and periods of amenorrhea (53.9 % vs. 46.2%, p = 0.06). Compared to controls, women in the CFS group had a higher mean number of pregnancies (2.8 vs 2.0, p = 0.05) and gynecological surgeries (1.8 vs. 1.1, p = 0.05). Similar proportions of the CFS (69.4%) and control (72.9%) groups were menopausal. Although menopausal women in the CFS and control groups had similar mean age (55.5 and 55.8, respectively), menopause occurred about 4.4 years earlier in the CFS group (41.7 years vs. 46.1 years, respectively, p = 0.11). Among menopausal women, 76% of the CFS group reported hysterectomy vs. 54.6% of controls (p = 0.09), and 56% of women with CFS reported oophorectomy vs. 34.3% of controls (p = 0.11).

CONCLUSIONS: The higher prevalence of gynecological conditions and gynecological surgeries in women with CFS highlights the importance of evaluating gynecological health in these patients and the need for more research to clarify the chronologic and the pathophysiological relationships between these conditions and CFS.

Source: Boneva RS, Maloney EM, Lin JM, Jones JF, Wieser F, Nater UM, Heim CM, Reeves WC. Gynecological history in chronic fatigue syndrome: a population-based case-control study. J Womens Health (Larchmt). 2011 Jan;20(1):21-8. doi: 10.1089/jwh.2009.1900. Epub 2010 Nov 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017420/ (Full article)

Gut inflammation in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood.

Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder’s pathogenesis.

Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease.

In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut. If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder.

For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.

Source: Lakhan SE, Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010 Oct 12;7:79. doi: 10.1186/1743-7075-7-79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964729/ (Full article)

Chronic fatigue syndrome reflects loss of adaptability

In this issue, Van Oosterwijck et al. [1] report that physical exercise lowered pain thresholds and was associated with exacerbation of symptoms in patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) whereas, on the other hand, postexercise activity levels did not significantly decrease. Based on these and similar findings in patients with CFS, we present a conceptual framework that might provide a better understanding of the key features and pathophysiological mechanisms of CFS, and thus improve its diagnosis and treatment.

CFS as a failure of allostasis?

Van Oosterwijck et al. [1] correctly note the frequent cooccurrence of a chronic ‘fatigue–pain’ symptom cluster, usually diagnosed as CFS and/or fibromyalgia. Recently, it has been proposed that this cluster should be classified under the unifying label of ‘central sensitivity syndromes’– a broad range of functional somatic disorders mainly characterized by common sensory abnormalities (i.e. widespread pain, hyperalgesia, allodynia and hypersensitivity to noise, bright light and certain chemical substances) [2].

However, ‘stress intolerance and pain hypersensitivity syndromes’ may be a more appropriate umbrella term for these syndromes because it reflects these patients’ inability to adequately adapt to all kinds of physical and mental stressors, including pathological pain processing [3]. Within the innovative neurobiological stress paradigm of ‘allostasis’– the need for stability through continuous change [4] – this general loss of adaptability may be understood as a failure of allostasis.

Although the mechanisms underlying this failure are still unclear, they may include complex and interrelated disturbances of different components of the stress system, (i.e. the hypothalamic–pituitary–adrenal (HPA) axis), the sympathetic nervous system and various neurotransmitters that modulate perceptual–cognitive and affective brain circuits, all of which operate in intimate connection with the immune system and central pain mechanisms [5].

We and others have hypothesized that the pathophysiology of CFS might include a ‘switch’ from HPA axis hyperfunction to hypofunction following a period of chronic physical and/or psychosocial stress in vulnerable persons resulting in inadequate cortisol reactivity which may in turn, via low glucocorticoid signalling, increase inflammatory activity [5]. This assumption is consistent with the relatively low basal cortisol levels and blunted diurnal cortisol rhythm frequently observed in CFS patients [5], but recent data suggest that a decrease in glucocorticoid receptor sensitivity might play a role as well [6].

Abnormal activation of innate immunity involves the release of pro-inflammatory cytokines that influence the brain and give rise to ‘sickness behaviour’. This evolutionary, physiological and behavioural reaction normally occurs during infection or severe injury and its purpose is to optimally fight bodily threats by reorganizing priorities, saving energy and promoting healing and recovery. Characteristic symptoms are profound lethargy, feelings of malaise, concentration difficulties, headache, mild fever, sensory hypersensitivity and generalized pain. In CFS patients, however, this ‘flu-like’ symptom complex may be typically provoked by any kind of stressor (e.g. physical effort, mental pressure, strong emotions) and lead to a motivational shift by urging the patient to withdraw from activities [7].

Yet, the situation may be more complex. Not only is there evidence for basal hyperfunction of the sympathetic nervous system in CFS [8] and fibromyalgia [9], but dysfunctional descending pain-inhibiting pathways [10] and various psychological mechanisms may also contribute to abnormal pain perception [11].

The data presented by Van Oosterwijck et al. [1] fit within the stress adaptability hypothesis, which includes immune-related central pain sensitization, and thus make a strong case for refining current diagnostic criteria of CFS [12] to incorporate – as a mandatory criterion –patients’ maladaptive postexertional response. Novel clinical diagnostic criteria have meanwhile been developed [13] but it remains to be seen whether these criteria will empirically prove to be appropriate in identifying the key features of the illness.

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02240.x/full

Comment on: Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. [J Intern Med. 2010]

Source: Van Houdenhove B, Luyten P. Chronic fatigue syndrome reflects loss of adaptability. J Intern Med. 2010 Sep;268(3):249-51. doi: 10.1111/j.1365-2796.2010.02240.x. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02240.x/full (Full article)

An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways

Abstract:

There is a significant ‘comorbidity’ between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy.

This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2′-5′ oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS.

Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways.

Depression and ME/CFS are not ‘comorbid’ disorders, but should be regarded as ‘co-associated disorders’ that are clinical manifestations of shared pathways.

Source: Maes M. An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):784-94. doi: 10.1016/j.pnpbp.2010.06.023. Epub 2010 Jul 4. https://www.ncbi.nlm.nih.gov/pubmed/20609377

A panel of biomarkers accurately identifies CFS/ME patients and contributes to the understanding of the pathophysiology of the disorder

Abstract:

Background: CFS/ME is a debilitating illness for which no specific biomarkers have been identified, although several immune abnormalities including neuroinflammation have been described. The goal of this study was to assemble a panel of immune and inflammatory markers, with the ability to accurately identify CFS/ME cases.

Objectives: From observations made in clinical practice, four markers were selected (immune and inflammatory). These markers were initially investigated to establish differences between CFS/ME cases and controls. We then evaluated their potential usefulness as a diagnostic biomarker by establishing their specificity and sensitivity.

Methods: Venous blood was collected from 70 male and 70 female CFS/ME patients (mean age 43 and 44 years, respectively – Fukuda case definition was used) as well as 70 male and 70 female healthy controls (mean age 43.5 and 44.5 years, respectively).

Serum Interleukin 8 (IL-8), soluble CD14 (sCD14, a surrogate marker for bacterial LPS), and prostaglandin E2 (PGE2) were measured for all subjects as were absolute CD3- / CD57+ lymphocytes counts (CD57+ lymph), according to accepted clinical laboratory techniques.

We then established median values for all analysed parameters; independent sample t-test, Mann-Whitney test and ROC curve analysis were used to investigate difference linked to gender and age.

Results: ROC Statistics (area under the ROC curve) revealed a significant difference between CFS/ME cases and controls (p <0.001) for the four parameters separately, both in the male and female cohorts. Sensitivity was 74.3 – 80 % (females) and 52.1 – 85.9 % (males). Specificity was 57.1 – 98.1 (females) and 65.7 – 88.6 (males).

Logistic regression analysis for the combination of parameters in our panel (IL-8, sCD14, PGE2 and CD57+ lymph) correctly predicted in 89.36 % of male CFS/ME cases and in 97.14 % of female CFS/ME cases.

Conclusions: This panel differentiates CFS/ME cases from controls with high sensitivity and specificity and therefore represents a potential tool in selecting CFS/ME subjects for clinical studies. Each of these four biological markers relate strongly to the disorder.

PGE2 activates dendritic cells and suppresses their ability to attract T cells. It also suppresses the function of macrophages and neutrophils as well as Th1, CTL-, NK-cell mediated type 1 immunity (e.g. CD3- / CD57+ lymphocytes). PGE2 additionally promotes Th2, Th17 and Tregs and also modulates chemokine production (e.g. IL-8).

When taken together, these data suggest that lipopolysaccharide (LPS), likely from gut bacteria, plays an important role in the pathophysiology of CFS/ME.

This screening panel represents an initial step toward identifying biomarkers to broadly diagnose subjects with CFS/ME.

Subsequent markers will be required to subcategorize CFS/ME subjects in order to tailor therapeutic solutions.

Source: Kenny L. De Meirleir1,2, Tatjana Mijatovic3, Eugene Bosmans3, Nossa Van den Vonder2, Vincent Lombardi1. A panel of biomarkers accurately identifies CFS/ME patients and contributes to the understanding of the pathophysiology of the disorder. Abstract from IACFS/ME Conference 2016 Program.

1. Nevada Center for Biomedical Research at University
of Nevada, Reno, USA
2. Himmunitas vzw, Brussels, Belgium
3. RED Laboratories NV, Zellik, Belgium

Are symptoms of ‘hypoglycemia’ in Chronic Fatigue Syndrome (CFS) associated with hypoglycemia or orthostatic intolerance in young people?

Background: Symptoms of nausea, feeling faint, malaise and mild anxiety are common in young people with CFS and popularly attributed to ‘hypoglycemia’ resulting in various dietary interventions with little reported improvement.

Objectives: To determine whether the symptoms are associated with measured hypoglycaemia using continuous tissue glucose monitoring or whether these symptoms are associated with documented orthostatic intolerance.

Methods: Nine young people with CFS (mean age 20 years) and mean duration of 4.5 years with persistently troublesome symptoms were compared with 10 healthy adult controls without diabetes. Each subject agreed to 3 days Continuous Glucose Monitoring System (Medtronic CGMS). This is routinely used in adolescent diabetics to document food intake, tissue glucose levels and activity levels to monitor control.

Subsequently 8 of these had formal cardiac tilt table testing where heart rate and blood pressure are measured supine and during 70 degree head-up tilt for up to 10 minutes to assess the presence orthostatic intolerance (either postural orthostatic tachycardia (POTS) or neurocardiogenic hypotensive syndrome). If positive, appropriate medical management of increasing salt and fluids, gentle improvement of muscle tone and blood pressure support medications, was implemented.

Results: The tissue glucose was calibrated with the blood glucose and all fell within acceptable normal range. There was statistical (but not clinical) significance in average tissue glucose in CFS subjects. 6% of time in controls and 16.8% in CFS was spent in the range <4mmol/L glucose (95% CI -23% to +2%, p=0.1) suggesting weak evidence for a difference given the variability and small sample size. The reported presence of symptoms throughout the day was not associated with significant reduction in tissue glucose levels.

Six had confirmed evidence for POTS, one for neurocardiogenic syndrome and one for a combination of both. All 8 reported improvement in all symptoms especially nausea, dizziness and malaise with active treatment of their orthostatic intolerance.

Conclusion: This study could not confirm a link between putative symptoms of ‘hypoglycemia’ and documented hypoglycemia. This suggests that symptoms frequently attributed to ‘hypoglycemia’ may be due to orthostatic intolerance and further investigation and management of this condition provides more reported relief for these troublesome symptoms.

Dr Kathy Rowe, Senior Consultant Paediatrician, Department of General Medicine, Royal Children’s Hospital, Melbourne, Victoria, Australia 3052
kathy.rowe@rch.org.au No conflicts of interest to declare. RCH internally funded.

Source: Katherine Rowe, Rebecca Gebert, Susan Donath, Angas Hamer & Fergus Cameron. Are symptoms of ‘hypoglycemia’ in Chronic Fatigue Syndrome (CFS) associated with hypoglycemia or orthostatic intolerance in young people? From: The IACFS/ME 2016 Conference Syllabus.

Assessment of Cellular Bioenergetics in Chronic Fatigue Syndrome

Introduction: Abnormalities in bioenergetic function have been cited as one possible cause for chronic fatigue syndrome (CFS). One hypothesis to explain this suggests that CFS may be caused, at least in part, by an acquired mitochondrial dysfunction.

Extracellular flux analysers make real-time, in vitro assessment of cellular energy pathways possible. Using this technology, mitochondrial function can be measured in a variety of cell types in real-time thus increasing our understanding of the role of metabolism in CFS.

Objectives: This project aims to utilise extracellular flux detection technology in order to investigate the cellular bioenergetics of different cell types obtained from CFS patients and healthy controls.

Methods: Mitochondrial stress tests were conducted using skeletal muscle cells and peripheral blood mononuclear cells (PBMCs) derived from CFS patients and controls. During this test mitochondrial complexes are inhibited in turn to modulate respiration so mitochondrial function can be evaluated. The oxygen consumption rate of cells is measured which allows keys parameters of mitochondrial function to be measured and calculated in a single experiment, providing an overall assessment of mitochondrial function. Parameters measured are: basal respiration, maximal respiration and non-mitochondrial respiration. Proton leak, ATP-production and spare respiratory capacity are subsequently able to be calculated using the three measured parameters. CFS patients whose samples were used in these studies were diagnosed using the Fukuda definition.

Results: Results using skeletal muscle cells obtained from CFS patients (n=3) and controls (n=5), indicate that there is no difference in the energy profiles of the skeletal muscle cells of CFS patients in any of the parameters investigated.

Mitochondrial stress test results using PBMCs show CFS PBMCs (n=7) to be significantly lower than control cells (n=10) in all parameters investigated (p≤0.016). Importantly, these results suggest that CFS PBMCs perform closer to their maximum under normal conditions. This means that when CFS PBMCs come under stress they are less able to increase their respiration rate to compensate for the increase in stress.

Conclusions: These findings provide an interesting starting point for investigations into cellular bioenergetics in CFS.

Cara Jasmine Tomas; First year medical science PhD student; Institute of Cellular Medicine, Level 1, William Leech Building, Medical School, Newcastle University, Newcastle Upon-Tyne, NE2 4HH, England; c.j.tomas@ncl.ac.uk
This work was funded by the Medical Research Council and Newcastle University.

Source: Cara Tomas, Julia Newton, Audrey Brown, Gina Rutherford, Philip Manning
Newcastle University, UK. Assessment of Cellular Bioenergetics in Chronic Fatigue Syndrome. Poster presentation, IACFS/ME 2016 conference.

Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways

Abstract:

BACKGROUND: In a recently published paper, Harvey and Wessely put forward a ‘biopsychosocial’ explanatory model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is proposed to be applicable to (chronic) fatigue even when apparent medical causes are present.

METHODS: Here, we review the model proposed by Harvey and Wessely, which is the rationale for behaviourally oriented interventions, such as cognitive behaviour therapy (CBT) and graded exercise therapy (GET), and compare this model with a biological model, in which inflammatory, immune, oxidative and nitrosative (IO&NS) pathways are key elements.

DISCUSSION: Although human and animal studies have established that the pathophysiology of ME/CFS includes IO&NS pathways, these abnormalities are not included in the model proposed by Harvey and Wessely. Activation of IO&NS pathways is known to induce fatigue and somatic (F&S) symptoms and can be induced or maintained by viral and bacterial infections, physical and psychosocial stressors, or organic disorders such as (auto)immune disorders. Studies have shown that ME/CFS and major depression are both clinical manifestations of shared IO&NS pathways, and that both disorders can be discriminated by specific symptoms and unshared or differentiating pathways. Interventions with CBT/GET are potentially harmful for many patients with ME/CFS, since the underlying pathophysiological abnormalities may be intensified by physical stressors.

CONCLUSIONS: In contrast to Harvey and Wessely’s (bio)psychosocial model for ME/CFS a bio(psychosocial) model based upon IO&NS abnormalities is likely more appropriate to this complex disorder. In clinical practice, we suggest physicians should also explore the IO&NS pathophysiology by applying laboratory tests that examine the pathways involved.

Source: Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15;8:35. doi: 10.1186/1741-7015-8-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901228/ (Full article)