Pathogenetic Mechanism and Potential Therapeutic Targets for Fatigue in Primary Biliary Cirrhosis (PBC)

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

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.

Publications

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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

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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

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Dyson JK (2015) Novel therapeutic targets in primary biliary cirrhosis. in Nature reviews. Gastroenterology & hepatology

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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

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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

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European Association For The Study Of The Liver (2009) EASL Clinical Practice Guidelines: management of cholestatic liver diseases. in Journal of hepatology

 
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) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 10/2014
 
Description EME
Amount £750,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 04/2015
 
Description ME Research UK funding
Amount £132,000 (GBP)
Organisation ME Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2011 
End 12/2012
 
Description Stratified Medicine
Amount £4,972,138 (GBP)
Funding ID MR/L001489/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2013 
End 11/2017
 
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 
Year Produced 2006 
Provided To Others? Yes  
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 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2008 
Provided To Others? Yes  
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
Start Year 2008
 
Description UK-PBC Research Consortium 
Organisation John Radcliffe Hospital
Department Department of Gastroenterology
Country United Kingdom 
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
Start Year 2008
 
Description UK-PBC Research Consortium 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
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
Start Year 2008
 
Description UK-PBC Research Consortium 
Organisation Queen Elizabeth Hospital Birmingham
Country United Kingdom 
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
Start Year 2008
 
Description UK-PBC Research Consortium 
Organisation University of Cambridge
Department Department of Medicine
Country United Kingdom 
Sector Academic/University 
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
Start Year 2008
 
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
Part Of Official Scheme? No
Geographic Reach National
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
Year(s) Of Engagement Activity 2008
URL http://www.library.nhs.uk/Pathways/SearchResults.aspx?searchText=cirrhosis&tabID=288
 
Description Patient Group Meetings 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
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 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
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
Year(s) Of Engagement Activity 2008