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

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.

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.