[Show abstract][Hide abstract] ABSTRACT: Background Fatigue is a debilitating condition with a significant impact on patients' quality of life. Fatigue is frequently reported by patients suffering from primary Sjogren's Syndrome (pSS), a chronic autoimmune condition characterised by dryness of the eyes and the mouth. However, although fatigue is common in pSS, it does not manifest in all sufferers, providing an excellent model with which to explore the potential underpinning biological mechanisms. Methods Whole blood samples from 133 fully-phenotyped pSS patients stratified for the presence of fatigue, collected by the UK primary Sjogren's Syndrome Registry, were used for whole genome microarray. The resulting data were analysed both on a gene by gene basis and using pre-defined groups of genes. Finally, gene set enrichment analysis (GSEA) was used as a feature selection technique for input into a support vector machine (SVM) classifier. Classification was assessed using area under curve (AUC) of receiver operator characteristic and standard error of Wilcoxon statistic, SE(W). Results Although no genes were individually found to be associated with fatigue, 19 metabolic pathways were enriched in the high fatigue patient group using GSEA. Analysis revealed that these enrichments arose from the presence of a subset of 55 genes. A radial kernel SVM classifier with this subset of genes as input displayed significantly improved performance over classifiers using all pathway genes as input. The classifiers had AUCs of 0.866 (SE(W) 0.002) and 0.525 (SE(W) 0.006), respectively. Conclusions Systematic analysis of gene expression data from pSS patients discordant for fatigue identified 55 genes which are predictive of fatigue level using SVM classification. This list represents the first step in understanding the underlying pathophysiological mechanisms of fatigue in patients with pSS.
[Show abstract][Hide abstract] ABSTRACT: Background:
Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.
Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.
In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16 h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16 h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.
EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial. This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue.
Methods and analysis:
RITPBC is a Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (EME)-funded project. It is a phase II, single-centre, randomised controlled, double-blinded trial comparing rituximab with placebo in fatigued PBC patients. 78 patients with PBC and moderate to severe fatigue will be randomised to receive two infusions of rituximab or placebo. The study aims to assess whether rituximab improves fatigue in patients with PBC, the safety, and tolerability of rituximab in PBC and the sustainability of any beneficial actions. The primary outcome will be an improvement in fatigue domain score of the PBC-40, a disease-specific quality of life measure, evaluated at 12-week assessment. Secondary outcome measures include novel MRS techniques assessing muscle bioenergetic function, physical activity, anaerobic threshold and symptom, and quality of life measures. The trial started recruiting in October 2012 and recruitment is ongoing.
Ethics and dissemination:
The trial has ethical approval from the NRES Committee North East, has Clinical Trial Authorisation from MHRA and local R&D approval. Trial results will be communicated to participants, presented at national and international meetings and published in peer-reviewed journals.
Trial registration number:
Full-text · Article · Apr 2015 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Background & AimsPatients with primary sclerosing cholangitis (PSC) frequently highlight the impact of fatigue on their life quality. The study aims were to evaluate fatigue and its associations in PSC and investigate whether overt autonomic dysfunction contributes to the expression of fatigue.Methods
All PSC patients under active follow-up at a regional liver centre were sent disease- and symptom-assessment tools. Three control groups were utilised; unselected community controls, patients with inflammatory bowel disease (IBD) without PSC, and cholestatic controls with primary biliary cirrhosis (PBC). A representative subgroup of PSC patients and normal controls underwent formal autonomic assessment.ResultsSymptom-assessment tools were returned by 40 non-transplanted patients. PSC patients had significantly worse fatigue than population controls (p=0.005). Fatigue was significant compared to population controls whether or not patients had accompanying IBD, although was more marked in those with both PSC and IBD. In patients with PSC and IBD, fatigue severity and autonomic symptoms were significantly increased in those with prior significant surgical intervention. Clinically significant autonomic dysfunction was seen in 22.5% of PSC patients, and of those, 78% had significant fatigue. Neurally-mediated hypotension was found in 60% of PSC patients compared to 8% in the control group. The PSC group had increased sympathetic activity and reduced parasympathetic activity.Conclusion
Fatigue is a significant problem in a minority of PSC patients and appears to be associated with autonomic dysfunction. Fatigued PSC patients should be screened for autonomic dysfunction and targeting such dysfunction represents a potential approach to treatment which warrants further exploration.This article is protected by copyright. All rights reserved.
No preview · Article · Nov 2014 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterised by a breakdown of immune tolerance to mitochondrial and nuclear antigens, causing injury to the biliary epithelial cells (BEC) lining the small intrahepatic bile ducts. This leads to bile duct injury and the retention of hydrophobic bile acids which cause further BEC injury leading to a self-sustaining cycle of bile duct injury. Initially the BEC respond to injury via a homeostatic response including through proliferation. Ultimately they become senescent; an active process with accompanying release of inflammatory cytokines ('the senescent secretome') which contributes to the process of interface hepatitis which is a feature of high-risk and treatment-unresponsive disease. This model for pathogenesis of PBC has implications for potential therapy approaches in targeting both the 'upstream' immune injury and 'downstream' BEC response to the immune injury. Fatigue is the commonest reported symptom in PBC and has a negative impact on patients' perceived quality of life, often through social isolation. It is unrelated to the severity of liver disease and appears unresponsive to current therapies, including ursodeoxycholic acid and transplantation. Fatigue in PBC is complex, with numerous associated peripheral and CNS features. Initially, cholestasis causes degenerative CNS change affecting areas of the brain regulating autonomic dysfunction and sleep, and these changes lead directly to some manifestations of fatigue and the associated cognitive impairment. In addition to this, the anti-mitochondrial antibody has direct muscle level metabolic effects leading to over-utilisation of anaerobic metabolism. Autonomic dysfunction contributes to the impact of this metabolic change by limiting the capacity of the muscle to respond through increased proton/lactate efflux from cells and outflow from tissues. The model has a number of implications for potential therapy approaches.
No preview · Article · Jul 2014 · Digestive Diseases
[Show abstract][Hide abstract] ABSTRACT: Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.
Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.
Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope–labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.
Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).
Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid. This trial was registered at clinicaltrials.gov as NCT02135393.
Full-text · Article · Jun 2014 · American Journal of Clinical Nutrition
[Show abstract][Hide abstract] ABSTRACT: We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.
[Show abstract][Hide abstract] ABSTRACT: We explored patients' experiences of receiving a diagnosis of the liver disease primary biliary cirrhosis (PBC) through qualitative interviews. Findings were used to develop a patient information DVD with expert clinicians describing PBC and patients talking about their experiences. The DVD was premièred to an audience of PBC, patients who provided positive feedback. This research identified areas leading to a positive diagnosis experience, such as knowledge, information, consistency, a positive approach, simplification and repetition. We believe that introducing such a DVD into clinical practice, following diagnosis, will make a real difference to the quality of life of newly-diagnosed PBC patients.
No preview · Article · Mar 2011 · Journal of Visual Communication in Medicine
[Show abstract][Hide abstract] ABSTRACT: In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10⁻⁸) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.
[Show abstract][Hide abstract] ABSTRACT: Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally, we determine the relationship of these indices to the symptoms of PBC.
16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF).
PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF.
PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).
No preview · Article · Dec 2010 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Long-term outcome in primary biliary cirrhosis (PBC) remains unclear. Whilst response to ursodeoxycholic acid (UDCA) is associated with good outcome, this effect is not universal. Early data from our group have suggested that one factor associated with a poorer outcome in PBC is fatigue. The aim of this study was to explore the inter-relationship between UDCA use, response, and fatigue in determining outcome over 9 years in a unique, comprehensive patient cohort.
Longitudinal prospective study of a geographically-defined complete cohort of PBC patients in North-East England and matched community controls.
Survival to death or transplant was significantly lower in PBC patients than in the case-control population (88/136 (65%) v 114/136 84% (p<0.001 by log-rank test), with better survival in UDCA responders (defined using the Paris criteria) than in patients not treated with UDCA at study outset. Compared to the whole control group survival was reduced in PBC patients fatigued at study outset but not in those without fatigue (p<0.0001); an effect independent of the beneficial effect of UDCA response and of conventional parameters of liver disease severity. UDCA responders without fatigue at the study outset had a 9 year survival which was identical to controls. Patients without fatigue at the study outset who developed fatigue during follow-up had significantly worse survival than patients who remained without fatigue throughout (p<0.05). Fatigued controls had worse survival than non-fatigued controls (p = 0.05).
Survival in a comprehensive cohort of PBC patients is substantially reduced compared with case-matched community controls. Development of fatigue and non-treatment with UDCA were specifically (and independently) associated with increased risk of death in PBC.
No preview · Article · Nov 2010 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Introduction Recent follow-up cohort studies have identified biochemical parameters in UDCA-treated patients which identify “responders” with survival identical to normal control populations, in contrast to “non-responders” who have survival indistinguishable from that predicted by the Mayo Risk Score for untreated patients. The most widely accepted criteria for UDCA “response”, proposed by Corpechot, consist of alkaline phosphatase (ALP) <3× uln, alanine transaminase (ALT) <2× uln and bilirubin <1× uln. However, Bilirubin and ALP levels are independent predictors of outcome in PBC irrespective of UDCA treatment. ALT, in addition, is a biomarker for overlap syndrome, a prognostic feature itself.Aim UDCA response criteria identify a group of patients with an inherently low risk rather than UDCA response per se.Method In a comprehensive cohort of patients, geographically defined in 1999 followed up for 10 years, a group of patients (n=94) not treated with UDCA were identified. This cohor
[Show abstract][Hide abstract] ABSTRACT: To determine whether the magnetization transfer ratio (MTR) of the globus pallidus (GP) in patients with primary biliary cirrhosis (PBC) correlates with age, disease stage, and fatigue, using T(1) and T(2) mapping to determine whether the mechanism of change is consistent with manganese deposition in the GP as suggested by previous reports.
In all, 30 early-stage PBC patients, four end-stage PBC patients, and 14 female controls were recruited to age-matched groups. MTR, T(1) and T(2) measurements were performed. A bilateral region of interest (ROI)-based analysis was used to calculate GP MTR, T(1), and T(2) values. These were correlated with age, disease status, and fatigue.
MTR measurements showed a significant, negative correlation with age for controls and early-stage PBC patients, a positive correlation with T(2), and no correlation with T(1). Only GP T(2) is significantly lower in early-stage PBC patients than controls, while end-stage patients demonstrated a simultaneous reduction in T(1) and MTR, consistent with GP manganese deposition.
MTR measurements correlate with age in both early-stage patient and control groups, but are not associated with manganese deposition or fatigue severity: only the end-stage disease group shows changes in MTR, T(1), T(2) that are consistent with manganese deposition.
Preview · Article · Apr 2009 · Journal of Magnetic Resonance Imaging