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.
Organisations
- 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)
- King's College London, United Kingdom (Collaboration)
- Queen Elizabeth Hospital Birmingham (Collaboration)
Publications

Alrubaiy L
(2019)
PBC-10: a short quality of life measure for clinical screening in primary biliary cholangitis
in Alimentary Pharmacology & Therapeutics

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
(2016)
The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.
in Alimentary pharmacology & therapeutics

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

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
Description | Contribution to education |
Geographic Reach | National |
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 | Public |
Country | United Kingdom |
Start | 10/2012 |
End | 10/2014 |
Description | EME |
Amount | £750,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 | Obetichololic Acid for Cognitive Symptoms: The OACS Trial Programme |
Amount | £2,500,000 (GBP) |
Organisation | Intercept Pharmaceuticals |
Sector | Private |
Country | United States |
Start | 04/2020 |
End | 12/2024 |
Description | Stratified Medicine |
Amount | £4,972,138 (GBP) |
Funding ID | MR/L001489/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 | Switzerland |
Sector | Charity/Non Profit |
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 | 2006,2007,2009,2012,2013,2014 |
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 |