Category: Pathophysiology

Autoantibodies to Selenoprotein P in Patients with Chronic Fatigue Syndrome Suggest Selenium Transport Impairment and Acquired Resistance to Thyroid Hormone

Abstract:

Chronic Fatigue Syndrome (CFS) presents with symptoms similar to hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, the typical thyroid hormone (TH) profile of elevated thyrotropin (TSH) and low thyroxine (T4) is not observed. Recently, autoantibodies to the selenium transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto’s thyroiditis and shown to impair selenium transport and selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS and impair TH metabolism.

Selenium status in CFS (n=167) was compared to that of healthy controls (n=545). Two additional small groups were included, namely patients with fibromyalgia (FM; n=39), a disease often comorbid with CFS, and patients with post-COVID condition (n=24). The serum/plasma Se biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP levels showed linear correlations without reaching saturation, indicative of Se deficiency. TSH and total T4 levels fitted within normal ranges, but relative total T3 (%TT3) was low, and relative rT3 (%rT3) was elevated in CFS. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity.

An impairment of Se transport in SELENOP-aAb positive CFS patients is suggested by the lack of correlation between total Se and GPx3 activity. The same patients present with disturbed TH parameters, including low deiodinase (DIO) activity (SPINA-GD index) and particularly low urinary iodine as compared to controls (43.2 (16.0) vs. 89.0 (54.9) µg/L, P<0.001), indicating that SELENOP-aAb affect TH deiodination and iodine excretion.

We conclude that a considerable subset of CFS patients express SELENOP-aAb that disturb Se transport and cause low GPx3 and DIO activities. Hereby, TH deiodination decreases as an acquired condition that is not readily reflected by TSH or T4 in blood. This hypothesis opens new explanations and therapeutic options for SELENOP-aAb positive CFS and, perhaps, post-COVID condition patients, but requires additional clinical evidence from intervention trials.

Source: Sun, Qian and Oltra, Elisa and Dijck-Brouwer, D. A. Janneke and Chillon, Thilo Samson and Seemann, Petra and Asaad, Sabrina and Demircan, Kamil and Espejo-Oltra, José Andrés and Sánchez-Fito, Teresa and Martin-Martinez, Eva and Minich, Waldemar B. and Muskiet, Frits A. J. and Schomburg, Lutz, Autoantibodies to Selenoprotein P in Patients with Chronic Fatigue Syndrome Suggest Selenium Transport Impairment and Acquired Resistance to Thyroid Hormone. Available at SSRN: https://ssrn.com/abstract=4332223 or http://dx.doi.org/10.2139/ssrn.4332223 (Full text available as PDF file)

Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Highlights:

  • Adults with ME/CFS experience a 3-fold greater reduction in cerebral blood flow during end-tilt tilt compared to healthy controls, confirming orthostatic intolerance.
  • During tilt testing we found that in 134/362 (37%) patients with ME/CFS without POTS or hypotension, the heart rate increase was below the lower limit of the 95% prediction interval of the heart rate increase of controls, indicative of orthostatic chronotropic incompetence.
  • These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing, confirming another abnormality in the circulatory response to upright posture in ME/CFS.

Abstract:

Background: Orthostatic intolerance (OI) is a core diagnostic criterion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The majority of ME/CFS patients have no evidence of hypotension or postural orthostatic tachycardia syndrome (POTS) during head-up tilt, but do show a significantly larger reduction in stroke volume index (SVI) when upright compared to controls. Theoretically a reduction in SVI should be accompanied by a compensatory increase in heart rate (HR). When there is an incomplete compensatory increase in HR, this is considered chronotropic incompetence.

This study explored the relationship between HR and SVI to determine whether chronotropic incompetence was present during tilt testing in ME/CFS patients.

Methods: From a database of individuals who had undergone tilt testing with Doppler measurements for SVI both supine and end-tilt, we selected ME/CFS patients and healthy controls (HC) who had no evidence of POTS or hypotension during the test.

To determine the relation between the HR increase and SVI decrease during the tilt test in patients, we calculated the 95% prediction intervals of this relation in HC. Chronotropic incompetence in patients was defined as a HR increase below the lower limit of the 95th % prediction interval of the HR increase in HC.

Results: We compared 362 ME/CFS patients with 52 HC. At end-tilt, tilt lasting for 15 (4) min, ME/CFS patients had a significantly lower SVI (22 (4) vs. 27 (4) ml/m2; p<0.0001) and a higher HR (87 (11) vs. 78 (15) bpm; p<0.0001) compared to HC. There was a similar relationship between HR and SVI between ME/CFS patients and HC in the supine position.

During tilt ME/CFS patients had a lower HR for a given SVI; 37% had an inadequate HR increase. Chronotropic incompetence was more common in more severely affected ME/CFS patients.

Conclusion: These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing in ME/CFS patients.

Source: C. (Linda) M.C. van Campen, Freek W.A. Verheugt, Peter C. Rowe, Frans C. Visser. Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). IBRO Neuroscience Reports [In Press, Journal Pre-proof]  Available online 2 May 2023 https://www.sciencedirect.com/science/article/pii/S2667242123000374 (Full text)

Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a multisystem chronic illness characterized by severe muscle fatigue, pain, dizziness, and brain fog. Many patients with ME/CFS experience orthostatic intolerance (OI), which is characterized by frequent dizziness, light-headedness, and feeling faint while maintaining an upright posture.
Despite intense investigation, the molecular mechanism of this debilitating condition is still unknown. OI is often manifested by cardiovascular alterations, such as reduced cerebral blood flow, reduced blood pressure, and diminished heart rate. The bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of endothelial nitric oxide synthase (eNOS) enzyme, is tightly coupled with cardiovascular health and circulation.
To explore the role of BH4 in ME/CFS, serum samples of CFS patients (n = 32), CFS patients with OI only (n = 10; CFS + OI), and CFS patients with both OI and small fiber polyneuropathy (n = 12; CFS + OI + SFN) were subjected to BH4 ELISA. Interestingly, our results revealed that the BH4 expression is significantly high in CFS, CFS + OI, and CFS + OI + SFN patients compared to age-/gender-matched controls.
Finally, a ROS production assay in cultured microglial cells followed by Pearson correlation statistics indicated that the elevated BH4 in serum samples of CFS + OI patients might be associated with the oxidative stress response. These findings suggest that the regulation of BH4 metabolism could be a promising target for understanding the molecular mechanism of CFS and CFS with OI.
Source: Gottschalk CG, Whelan R, Peterson D, Roy A. Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study. International Journal of Molecular Sciences. 2023; 24(10):8713. https://doi.org/10.3390/ijms24108713 (Full text)

Modulation of Beta-Adrenergic Autoantibodies Over Time in Post-Viral ME/CFS is Related to Fatigue and Pain Symptoms

Abstract:

Background: Myalgic encephalomyelits/chronic fatigue syndrome (ME/CFS) is an acquired disease with symptoms of fatigue and pain. In pathogenesis, the induction of autoantibodies (AAB) against G-protein coupled receptors (GPCR), such as β-adrenergic receptors (β-AdR), has been suspected. GPCR-AAB correlate with symptom severity and autonomic dysfunction in ME/CFS.

Objectives: To describe symptoms and treatment of a patient presenting with infection-triggered ME/CFS demonstrating that levels of β-AdR-AAB underlie modulation over time, correlating with the severity of symptoms.

Methods: At T1 and T2, GPCR-AAB were measured and questionnaires assessing symptom severity were completed. TSHDS-IgM-AAB were tested, and SF density was analyzed via skin probe.

Results: At T2, elevated levels of β-AdR-AAB were found, corresponding with an aggravation of fatigue and pain symptoms. Elevated TSHDS-IgM-AAB were found, which corresponded with reduced fiber density from the skin probe.

Conclusions: The levels of β-AdR-AAB in post-infectious ME/CFS can be modulated. Future studies might target interventions to reduce these AAB.

Source: Busch L, Schriek C, Paul M, Heidecke H. Modulation of Beta-Adrenergic Autoantibodies Over Time in Post-Viral ME/CFS is Related to Fatigue and Pain Symptoms. Isr Med Assoc J. 2023 Apr;25(4):259-264. PMID: 37129123. https://pubmed.ncbi.nlm.nih.gov/37129123/

Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

  • Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
  • Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
  • Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
  • Enhanced IL-10 regulatory response may drive the observed immunosuppression.
  • Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.

Abstract:

The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear.

Relying on data from two independent cohorts of ME/CFS and control study participants, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

Source: Melanie Uhde, Alyssa C. Indart, Peter H.R. Green, Robert H. Yolken, Dane B. Cook, Sanjay K. Shukla, Suzanne D. Vernon, Armin Alaedini.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome. Brain, Behavior, & Immunity – Health, 2023, 100627. ISSN 2666-3546, https://doi.org/10.1016/j.bbih.2023.100627.
https://www.sciencedirect.com/science/article/pii/S2666354623000418 (Full text)

Exploring the Genetic Contribution to Oxidative Stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

OBJECTIVES/GOALS: Strong evidence has implicated oxidative stress (OS) as a disease mechanism in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The study aim was to assess whether a C>T single nucleotide polymorphism (SNP) (rs1800668), which reduces the activity of glutathione peroxidase 1 (GPX1), is associated with brain OS in patients with ME/CFS.

METHODS/STUDY POPULATION: Study population: The study enrolled 20 patients with ME/CFS diagnosed according to Canadian Consensus Criteria, and 11 healthy control (HC) subjects. Genotyping: DNA was extracted from whole blood samples, amplified by PCR, and purified. Sanger sequencing was used for genotyping. 1H MRS: Proton magnetic resonance spectroscopy (1H MRS) was used to measure levels of glutathione (GSH) a primary tissue antioxidant and OS marker in a 3x3x2 cm3 occipital cortex (OCC) voxel. GSH spectra were recorded in 15 minutes with the standard J-editing technique. The resulting GSH peak area was normalized to tissue water level in the voxel. Statistical Analysis: T-tests were used to compare OCC GSH levels between ME/CFS and HC groups, and between the study’s genotype groups (group 1: CC, group 2: combined TC and TT).

RESULTS/ANTICIPATED RESULTS: Clinical characteristics: ME/CFS and HC groups were comparable on age and BMI but not on sex (p = 0.038). Genotype frequencies: Genotype frequencies in the ME/CFS group were 0.55 (CC), 0.25 (TC) and 0.2 (TT); and 0.636 (CC), 0.364 (TC), and 0 (TT) in the HC group. GSH levels: There was a trend-level lower mean OCC GSH in ME/CFS than in HC (0.0015 vs 0.0017; p = 0.076). GSH levels by genotype group interaction: Within the ME/CFS group but not in the combined ME/CFS and HC group or HC group alone, GSH levels were lower in the TC and TT genotypes than in CC genotypes (0.00143 vs 0.00164; p = 0.018).

DISCUSSION/SIGNIFICANCE: This study found that the presence of a C>T SNP in GPX1 is associated with lower mean GSH levels and, hence, brain oxidative stress, in ME/CFS patients. If validated in a larger cohort, this finding may support targeted antioxidant therapy based on their genotype as a potentially effective treatment for patients with ME/CFS.

Source: Hampilos, N., Germain, A., Mao, X., Hanson, M., & Shungu, D. (2023). 474 Exploring the Genetic Contribution to Oxidative Stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical and Translational Science, 7(S1), 137-138. doi:10.1017/cts.2023.488. DOI: https://doi.org/10.1017/cts.2023.488

LC, POTS, and ME/CFS: Lifting the Fog

Abstract:

These three syndromes – long covid (LC), postural orthostatic tachycardia syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) – have many symptoms in common. The common denominator remains elusive.
The blood brain barrier (BBB) has been a barrier not only to microbes and toxins but also to understanding pathogenetic links. There are several areas within the brain that have no BBB. These are known as circumventricular organs (CVOs) and their location relative to CNS nuclei that direct autonomic and neuroendocrine functions is provocative in the quest for pathogenesis.
In addition the majority afflicted with LC and ME/CFS appear to be those with two MTHFR polymorphisms, present in over 50% of Americans. These polymorphisms elevate homocysteine. When homocysteine is combined with CVOs, the fog of POTS and its paradox are lifted. POTS may represent the intersection of LC and ME/CFS in those with the MTHFR gene (hypermethylation or 677TT).
The gut microbiomes of LC and ME/CFS, deficient in butyrates, GABA, and diversity, are then linked with MTHFR genotype 677TT. Reactivation of neurotropic EBV and VZV, due to loss of surveillance by CD4+/CD8+ T cells, is seen as secondary. The oxidative stress generated by homocysteine, loss of glutathione, low fiber diet, and persistent chronic inflammation exhaust available mitochondria and, assisted by BKN and estrogen, exacerbate all the elements of these post viral fatigue syndromes.
Source: Chambers, P. LC, POTS, and ME/CFS: Lifting the Fog. Preprints.org 2023, 2023030418. https://doi.org/10.20944/preprints202303.0418.v1 (Full text available as PDF file)

Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

Abstract:

ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS.

Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises.

Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction. Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms.

Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens.

Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system.

Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes.

Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.

Source: Jean M. Nunes, Douglas B. Kell, Etheresia Pretorius. Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses. Blood reviews, 20 March 2023, 101075 [Epub ahead of print]  https://www.sciencedirect.com/science/article/pii/S0268960X2300036X (Full text)

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation.

We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells.

We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.

Source: Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2023 Jan 19;24(3):2010. doi: 10.3390/ijms24032010. PMID: 36768336; PMCID: PMC9916395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916395/ (Full text)

Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM.
The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET). Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds.
Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline).
Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.
Source: Glass KA, Germain A, Huang YV, Hanson MR. Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients. International Journal of Molecular Sciences. 2023; 24(4):3685. https://doi.org/10.3390/ijms24043685 https://www.mdpi.com/1422-0067/24/4/3685 (Full text available as PDF file)