Category: Pathophysiology

Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study in primary care

Abstract:

BACKGROUND: Fatigue syndromes and irritable bowel syndrome (IBS) often occur together. Explanations include being different manifestations of the same condition and simply sharing some symptoms.

METHOD: A matched case-control study in UK primary care, using data collected prospectively in the General Practice Research Database (GPRD). The main outcome measures were: health-care utilization, specific symptoms and diagnoses. Risk markers were divided into distant (from 3 years to 1 year before diagnosis) and recent (1 year before diagnosis).

RESULTS: A total of 4388 patients with any fatigue syndrome were matched to two groups of patients: those attending for IBS and those attending for another reason. Infections were specific risk markers for both syndromes, with viral infections being a risk marker for a fatigue syndrome [odds ratios (ORs) 2.3-6.3], with a higher risk closer to onset, and gastroenteritis a risk for IBS (OR 1.47, compared to a fatigue syndrome). Chronic fatigue syndrome (CFS) shared more distant risk markers with IBS than other fatigue syndromes, particularly other symptom-based disorders (OR 3.8) and depressive disorders (OR 2.3), but depressive disorders were a greater risk for CFS than IBS (OR 2.4). Viral infections were more of a recent risk marker for CFS compared to IBS (OR 2.8), with gastroenteritis a greater risk for IBS (OR 2.4).

CONCLUSIONS: Both fatigue and irritable bowel syndromes share predisposing risk markers, but triggering risk markers differ. Fatigue syndromes are heterogeneous, with CFS sharing predisposing risks with IBS, suggesting a common predisposing pathophysiology.

 

Source: Hamilton WT, Gallagher AM, Thomas JM, White PD. Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study in primary care. Psychol Med. 2009 Nov;39(11):1913-21. doi: 10.1017/S0033291709005601. Epub 2009 Apr 15. https://www.ncbi.nlm.nih.gov/pubmed/19366500

 

Visible and near-infrared spectral changes in the thumb of patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) patients show a persistent fatigue condition with muscle pain and impairment of concentration, memory, and sleep. Presently, the physiological basis of CFS remains unclear. In this study, spectroscopic differences in the thumb were compared between 103 CFS patients and 122 healthy controls to examine possible changes of levels of oxygenated or deoxygenated hemoglobin.

METHODS: Visible and near-infrared (Vis-NIR) spectroscopy was used to examine possible changes in the region of 600-1100 nm.

RESULTS: Vis-NIR spectra showed sharp peaks at 694, 970 and 1060 nm and broad peaks in the regions of 740-760 and 830-850 nm. As these peaks are possibly related to oxyhemoglobin, cytochrome c oxidase and water, levels of these factors were compared between the two groups. Statistical analysis of the absorbance of Vis-NIR spectra showed a significant decrease in water content, a significant increase in oxyhemoglobin content, and a significant increase in the oxidation of heme a+a(3) and copper in cytochrome c oxidase in CFS patients.

CONCLUSIONS: These changes imply accelerated blood flow and energy metabolism in the thumbs of CFS patients.

 

Source: Sakudo A, Kato YH, Tajima S, Kuratsune H, Ikuta K. Visible and near-infrared spectral changes in the thumb of patients with chronic fatigue syndrome. Clin Chim Acta. 2009 May;403(1-2):163-6. doi: 10.1016/j.cca.2009.02.010. Epub 2009 Feb 25. https://www.ncbi.nlm.nih.gov/pubmed/19248775

 

Can sustained arousal explain the Chronic Fatigue Syndrome?

Abstract:

We present an integrative model of disease mechanisms in the Chronic Fatigue Syndrome (CFS), unifying empirical findings from different research traditions. Based upon the Cognitive activation theory of stress (CATS), we argue that new data on cardiovascular and thermoregulatory regulation indicate a state of permanent arousal responses – sustained arousal – in this condition.

We suggest that sustained arousal can originate from different precipitating factors (infections, psychosocial challenges) interacting with predisposing factors (genetic traits, personality) and learned expectancies (classical and operant conditioning).

Furthermore, sustained arousal may explain documented alterations by establishing vicious circles within immunology (Th2 (humoral) vs Th1 (cellular) predominance), endocrinology (attenuated HPA axis), skeletal muscle function (attenuated cortical activation, increased oxidative stress) and cognition (impaired memory and information processing). Finally, we propose a causal link between sustained arousal and the experience of fatigue.

The model of sustained arousal embraces all main findings concerning CFS disease mechanisms within one theoretical framework.

 

Source: Wyller VB, Eriksen HR, Malterud K. Can sustained arousal explain the Chronic Fatigue Syndrome? Behav Brain Funct. 2009 Feb 23;5:10. doi: 10.1186/1744-9081-5-10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654901/ (Full article)

 

Secondary structural changes of proteins in fingernails of chronic fatigue syndrome patients from Fourier-transform infrared spectra

Abstract:

BACKGROUND: Generally, nails can be an index of health, with abnormalities sometimes found under diseased conditions. Fatigue is also supposed to affect the condition of nails. Possible differences in infrared (IR) spectra of nail plates of chronic fatigue syndrome(CFS) patients compared to healthy control subjects were investigated in this study.

METHODS: Using an attenuated total reflection (ATR)-Fourier-transform infrared (FTIR) spectrophotometer, spectra in the region of 4000-600 cm(-1) were obtained. The amide I region was then separated by Fourier deconvolution and curve fitting based on the Gauss and Lorentz formula and revealed differences in the secondary structural content of proteins compared to healthy donors.

RESULTS: The specific secondary structural pattern commonly observed in nails of male and female CFS patients in the absence and presence of medication indicated a decreased alpha-helix content and increased beta-sheet content, suggesting reduced levels of normal elements of the nail plate.

CONCLUSIONS: This provides the first evidence of alterations in the fingernails of CFS patients which could be detected by IR spectroscopy. Possible explanations for the alterations will be discussed.

 

Source: Sakudo A, Kuratsune H, Kato YH, Ikuta K. Secondary structural changes of proteins in fingernails of chronic fatigue syndrome patients from Fourier-transform infrared spectra. Clin Chim Acta. 2009 Apr;402(1-2):75-8. doi: 10.1016/j.cca.2008.12.020. Epub 2008 Dec 30. https://www.ncbi.nlm.nih.gov/pubmed/19150612

 

Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms

Abstract:

PURPOSE OF REVIEW: The aim of this paper is to review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in chronic fatigue and somatization disorder.

RECENT FINDINGS: Activation of IO&NS pathways is the key phenomenon underpinning chronic fatigue syndrome (CFS): intracellular inflammation, with an increased production of nuclear factor kappa beta (NFkappabeta), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS); and damage caused by O&NS to membrane fatty acids and functional proteins. These IO&NS pathways are induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-bacteria (leaky gut). The ‘psychosomatic’ symptoms experienced by CFS patients are caused by intracellular inflammation (aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection); damage caused by O&NS (aches and pain, muscular tension and fatigue); and gut-derived inflammation (complaints of irritable bowel). Inflammatory pathways (monocytic activation) are also detected in somatizing disorder.

SUMMARY: ‘Functional’ symptoms, as occurring in CFS and somatization, have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. The development of new drugs, aimed at treating those disorders, should target these IO&NS pathways.

 

Source: Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 Jan;22(1):75-83. https://www.ncbi.nlm.nih.gov/pubmed/19127706

 

Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) is one of the more complex illnesses involving multiple systems within the body. Onset of ME/CFS frequently occurs quickly, and many patients report a prior exposure to a viral infection. This debilitating illness can affect the immune, neuroendocrine, autonomic, and neurologic systems.

Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding the at times conflicting findings regarding the etiology and pathophysiology of this illness.

 

Source: Jason LA, Porter N, Herrington J, Sorenson M, Kubow S. Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Behav Neurosci Res. 2009 Jan 1;7(2):1-17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022475/ (Full article)

 

Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria

Abstract:

BACKGROUND: There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome(CFS).

METHODS: The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs.

RESULTS: Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).

DISCUSSION: The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.

 

Source: Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10. https://www.ncbi.nlm.nih.gov/pubmed/19112401

 

Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients

Abstract:

Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions including chronic immune activation, inflammation, and alteration of cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells.

We investigated the association between CFS and the frequency of rs763780, a C/T genetic polymorphism leading to His161Arg substitution in the IL-17F protein. The His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the wild-type IL-17F. A significantly lower frequency of the C allele was observed in the CFS population, suggesting that the His161Arg variant may confer protection against the disease. These results suggest a role of Th17 cells in the pathogenesis of CFS.

 

Source: Metzger K, Frémont M, Roelant C, De Meirleir K. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun. 2008 Nov 7;376(1):231-3. doi: 10.1016/j.bbrc.2008.08.135. Epub 2008 Sep 5. https://www.ncbi.nlm.nih.gov/pubmed/18774769

 

Treating Chronic Fatigue states as a disease of the regulation of energy metabolism

Abstract:

Chronic Fatigue Syndrome is a physiological state in which the patient feels high levels of fatigue without an obvious organic cause, which affects around 1 in 400 people in the developed world. A wide range of causes have been suggested, including immune or hormonal dysfunction, viral or bacterial infection, and psychological somatization. It is likely that several causes are needed to trigger the disease, and that the triggers are different from the mechanisms that maintain fatigue over months or years. Many treatments have been tested for CFS, with very limited success – a programme of combined CBT and graded exercise shows the most effect.

I suggest that patients with CFS have a reduced ability to increase mitochondrial energy production when exertion requires it, with fewer mitochondria that are each more efficient, and hence nearer to their maximum energy output, than normal. A range of indirect evidence suggests that the renin-angiotensin system stimulates mitochondrial responsiveness and reduces mitochondrial efficiency: chronic under-stimulation of this system could contribute to CFS aetiology.

If correct, this means that CFS can be successfully treated with RAS agonists (eg angiotensin mimetics), or adrenergic agonists. It also suggests that there will be a positive link between the use of adrenergic- and RAS-blocking drugs and CFS incidence, and a negative link between adrenergic agonist use and CFS.

 

Source: Bains W. Treating Chronic Fatigue states as a disease of the regulation of energy metabolism. Med Hypotheses. 2008 Oct;71(4):481-8. doi: 10.1016/j.mehy.2008.02.022. Epub 2008 Aug 5. https://www.ncbi.nlm.nih.gov/pubmed/18684570

 

An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS

Abstract:

BACKGROUND: It has been shown that chronic fatigue syndrome (CFS) and major depression (MDD) are accompanied by signs of oxidative stress and by a decreased antioxidant status. The aim of the present study was to examine whether CFS and MDD are accompanied by an IgM-mediated immune response directed against nitro-serum bovine albumin (BSA), which is a neoepitope of BSA formed by damage caused by nitrosative stress.

AIMS: Toward this end, we examined serum IgM antibodies to nitro-BSA in 13 patients with CFS, 14 subjects with partial CFS, 16 patients with MDD and 11 normal controls.

RESULTS: We found that the prevalence and mean values for the serum IgM levels directed against nitro-BSA were significantly greater in patients with partial CFS, CFS and MDD than in normal controls, and significantly greater in CFS than in those with partial CFS and MDD. We found significant and positive correlations between serum IgM levels directed against nitro-BSA and symptoms of the FibroFatigue scale, i.e. aches and pain and muscular tension. There was also a strong positive correlation between serum IgM titers directed against nitro-BSA and an index of increased gut permeability (“leaky gut”), i.e. serum IgM and IgA directed against LPS of different gram-negative enterobacteria.

DISCUSSION: The above mentioned results indicate that both CFS and MDD are accompanied by a) an increased gut permeability which has allowed an exaggerated passage of BSA through a compromised epithelial barrier; b) increased nitrosative stress which has induced damage to BSA; and c) an IgM-mediated immune response which is directed against the nitro-BSA neoepitopes. Nitrosative stress is one of the factors underpinning the comorbidity and clinical overlap between CFS and MDD.

 

Source: Maes M, Mihaylova I, Kubera M, Leunis JC. An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS. Neuro Endocrinol Lett. 2008 Jun;29(3):313-9. https://www.ncbi.nlm.nih.gov/pubmed/18580855