Pathogenetic Mechanism and Potential Therapeutic Targets for Fatigue in Primary Biliary Cirrhosis (PBC)
Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine
The chronic liver disease primary biliary cirrhosis (PBC), which affects up to 20,000 patients in the UK, is characterised by profound, often life-altering, fatigue. At present we neither understand why PBC patients get fatigue nor have any effective treatments for that fatigue. The aim of this project is to explore the mechanisms which are responsible for fatigue in PBC in order to identify potential new avenues for treatment. We intend to use new technologies to study brain function, peripheral muscle function (including the effectiveness of muscle when undertaking exercise) and the function of the autonomic system (the part of the nervous system that prepares the body for every-day function including exercise). Fatigue is a difficult symptom for patients, and one that generates much controversy. This study is unique in that it systematically studies a series of potential aetiological factors in the same patients, whilst including a control group of patients who suffer from the same underlying condition, but who do not experience the symptom. The ability to diagnose the disease in the absence of the symptom provides unique opportunities in the study of fatigue which are not available in conditions, such as chronic fatigue syndrome, where the presence of the symptom is required for disease diagnosis. PBC could therefore potentially represent a useful human model for the study of fatigue.
Technical Summary
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterised by profound fatigue which significantly reduces health-related quality of life (HRQOL) and which is currently untreatable. Our pilot studies have identified brain stem deposition of manganese, autonomic dysfunction (including loss of baroreflex sensitivity), suppression of the HPA axis, and reduced sustainability of skeletal muscle function as being features associated with the presence of fatigue in PBC patients. Moreover, prospective studies have suggested an increased mortality rate in fatigued PBC patients, principally resulting from an excess of sudden cardiac deaths. It is our hypothesis that CNS changes occur in response to cholestasis (or the inflammatory processes giving rise to cholestasis). The consequences of these CNS events include HPA suppression and autonomic dysfunction which have a net effect on perfusion and energy utilisation peripherally in muscle. In skeletal muscle this effect manifests itself as fatiguability and the sensation of fatigue, whilst in cardiac muscle it manifests itself as instability and a pre-disposition to sudden cardiac events. In the first phase of the study we will characterise the impact of fatigue on HRQOL on the whole North-Eastern UK PBC population (amongst the worlds largest and best characterised cohorts). This study will allow us to define high and low fatigue states and to identify appropriate subjects for the second phase of the study in which we will perform a comprehensive series of linked, innovative studies to address the biological basis of fatigue. MRI-based approaches will be used to characterise the CNS changes associated with fatigue and to directly study the bioenergetics of both skeletal and cardiac muscle. ?Upstream? CNS changes and ?downstream? muscle bioenergetic changes will be cross-correlated with comprehensive studies of autonomic function and of the HPA axis, including novel studies of the effects of 5HT releasing agents on this system imaged using an innovative MRI based approach developed for the project (abnormality of the hippocampal 5HT system has been strongly implicated in behavioural changes seen in cholestatic animal models). Comparison between otherwise matched fatigued and non-fatigued patients will allow us to develop a ?map? of the physiological changes associated with fatigue in PBC. Linear studies performed in patients listed for transplantation will also allow us to assess the reversibility of these changes post-transplant. These studies will provide a comprehensive and unique insight into the pathogenesis of fatigue, one of the most challenging problems faced by PBC patients and their carers.
Jun 06 - Sep 08
David Emrys Jones
Health Category:
Oral and Gastrointestinal (100%)
Research Activity:
2.1 Biological and endogenous factors (100%)
Newcastle University, United Kingdom (Lead Research Organisation)
European Association for the Study of the Liver (EASL) (Collaboration)
John Radcliffe Hospital, United Kingdom (Collaboration)
University of Cambridge, United Kingdom (Collaboration)
Queen Elizabeth Hospital Birmingham (Collaboration)
King's College London, United Kingdom (Collaboration)
David Emrys Jones (Principal Investigator)
Julia Newton (Co-Investigator)
Simon Bamforth (Co-Investigator)
Roy Taylor (Co-Investigator)
Anderson K (2013) Restless leg syndrome is a treatable cause of sleep disturbance and fatigue in primary biliary cirrhosis. in Liver international : official journal of the International Association for the Study of the Liver
Bhogal RH (2011) Anti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes. in Liver international : official journal of the International Association for the Study of the Liver
Carbone M (2013) The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. in Journal of hepatology
Carbone M (2013) Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. in Gastroenterology
Dyson J (2014) Diagnosis and management of patients with primary biliary cirrhosis. in Clinical liver disease
Dyson JK (2015) Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output. in Liver international : official journal of the International Association for the Study of the Liver
Dyson JK (2015) Novel therapeutic targets in primary biliary cirrhosis. in Nature reviews. Gastroenterology & hepatology
Dyson JK (2016) The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis. in Alimentary pharmacology & therapeutics
Elliott C (2011) Reduction in functional ability is significant postliver transplantation compared with matched liver disease and community dwelling controls. in Transplant international : official journal of the European Society for Organ Transplantation
Frith J (2010) Potential strategies to improve uptake of exercise interventions in non-alcoholic fatty liver disease. in Journal of hepatology
Further Funding
Research Tools and Methods
Products Interventions & Clinical Trials
Description Contribution to education
Geographic Reach UK
Policy Influence Type Influenced training of practitioners or researchers
Impact Appreciation of fatigue as a clinical problem, and target for treatment in its own right, in PBC ; Transformed the nature of the clinical problems associated with fatigue
Description European Treatment Guidelines
Geographic Reach Europe
Policy Influence Type Membership of a guidance committee
Impact I am a member of the European Association for the Study of the Liver (EASL) guideline for cholestatic liver disease (including PBC). These guidelines, which will be published shortly were informed in relation to fatigue management by my work ; First clinical guideline for PBC which acknowledges the importance of fatigue in the liver of patients and addresses its treatment
Description CFS Research Call
Amount £450,000 (GBP)
Organisation Medical Research Council (MRC)
Start 10/2012
End 10/2014
Description EME
Description ME Research UK funding
Organisation ME Research UK
Description Stratified Medicine
Amount £4,972,138 (GBP)
Funding ID MR/L001489/1
Title Fatigue Management Algorythm
Description Our successful development of symptom management algorhythms in liver disease have informed grant applications to develop a similar approach in other chronic diseases
Type Of Material Physiological assessment or outcome measure
Year Produced 2008
Provided To Others? Yes
Impact Grant applications in early renal disease to RfPB, thyroid disease to the Action Medical Research, Sjogrens to ARC. All utilise the methodologies developed in the MRC funded study.
Title PBC Clinical Cohort Database
Description Comprehensive database of the largest cohort of patients with PBC in the world, uniquely linking conventional data relating to disease severity and pathogenesis with symptom severity data (obtained using a novel disease- specific quality of life measure developed by my group (non-MRC funded)) and symptom aetiological process data
Type Of Material Database/Collection of Data/Biological Samples
Impact This tool proved that fatigue was not simply a consequence of conventional disease progression processes but is associated with distinct additional processes. The comprehensive nature of the dataset allowed novel links to be made (between, for example, fatigue and overt cognitive impairment) and an association between high symptom load and increased death rate to be made.
Title fMRI Assessment Protocol for Peripheral Muscle Function
Description Development of a new assessment protocol and exercise performance rig suitable for use in an MR scanner
Impact Published protocol for new technique allows standardisation of the approach
Description EASL Clinical Practice Guidelines Group for Cholestatic Liver Disease
Organisation European Association for the Study of the Liver (EASL)
Country European Union (EU)
Sector Learned Society
PI Contribution Provided original data to inform the development of relevant clinical guidelines
Collaborator Contribution Establishment of clinical treatment paradigms for fatigue in PBC
Impact Published clinical guidelines PubMed ID: 19501929
Description UK-PBC Research Consortium
Organisation John Radcliffe Hospital
Department Department of Gastroenterology
Sector Hospitals
PI Contribution The UK PBC research community has come together over the last 4 years in order to facilitate large-scale studies in PBC (www.UK-PBC.com). The first such study was a GWAS funded under Wellcome Trust WTCCC3 which recruited 5000 patients and which has published its results in 2 Nature Genetics papers. The next consortium project was to use the unique UK-PBC patient database to explore critical clinical questions in PBC. This work has highlighted the unmet clinical need in PBC in relation to failure of response to primary therapy with ursodeoxycholic acid (UDCA). The strength of the data (the UK-PBC cohort study which was presented at the American Association for the Study of Liver Diseases (AASLD) in 2012 and which is in re-submission to the field leading journal Gastroenterology) has informed a forthcoming submission to the MRC Stratified Medicine call and has attracted significant industry interest in PBC in general and in the UK as a location in which to undertake therapeutics work in PBC in particular. I am the Chief Investigator for UK-PBC and for the forthcoming MRC Stratified Medicine bid
Collaborator Contribution Recrutiment to studyPatient recruitmentPatient recruitmentPatient recruitment
Impact Two Nature Genetics publications Manuscript in re-submission to Gastroenterology
Organisation King's College London
Department School of Medicine KCL
Organisation Queen Elizabeth Hospital Birmingham
Organisation University of Cambridge
Department Department of Medicine
Title Integrated care pathway for PBC
Description Integrated care pathway for the management of PBC
Type Management of Diseases and Conditions
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2008
Development Status Closed
Impact This pathway allows the systematisation of the management of PBC and, critically, access to the optimal approach to management (including with a focus on symptom management and quality of life optimisation) to all patients regardless of whether they have access to a specialist clinic
Description Care Pathway
Form Of Engagement Activity A magazine, newsletter or online publication
Primary Audience Health professionals
Results and Impact The studies funded by this grant have informed the design of the fatigue/cognitive component of a novel integrated are pathway for PBC published in QJM (2008; 101:535-543) and in the National Library for Health http://www.library.nhs.uk/Pathways/SearchResults.aspx?searchText=cirrhosis&tabID=288 In our experience implementation of this pathway across a whole clinical service is associated with a significant overall improvement in patient quality of life (QJM as above).
Entering wide clinical use in the field
URL http://www.library.nhs.uk/Pathways/SearchResults.aspx?searchText=cirrhosis&tabID=288
Description Patient Group Meetings
Results and Impact PBC patient research update meetings. These are held around the region 6 times per year to explain our research, the rationale behind it, the key findings and what this means and may mean for the future improvements in treatment
In addition to their intrinsic worth these meetings hold substantial benefits in terms of recruitment rates for our studies.
Year(s) Of Engagement Activity 2006,2007,2009,2012,2013
Description Patient information leaflet & DVD
Results and Impact Our findings have informed new patient information media (conventional leaflets and a novel DVD) which explain "self-help" approaches to fatigue in PBC informed by our study. A paper describing the development and value to patients of this DVD has been accepted for publicatuion.
Highlighted by patient web fora internationally