Newcastle University is a world-renowned centre for research in hepatology. The Newcastle Magnetic Resonance Centre builds on this strength by offering unique non-invasive techniques for probing liver diseases.
Projects to date are addressing three important areas of liver research:
(i) The mechanisms of fatigue and autonomic dysfunction in Primary Biliary Cirrhosis (Dr Kieren Hollingsworth, Prof Andy Blamire and Prof Roy Taylor in collaboration with Prof David Jones and Dr Julia Newton, Institute for Cellular Medicine).
(ii) Assessing interventions for tackling fatty liver (hepatic steatosis) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) which may develop into Non-Alcoholic Steatohepatitis (Dr Kieren Hollingsworth, Dr Michael Trenell and Prof Roy Taylor in collaboration with Prof. Chris Day, School of Clinical Medical Sciences)
(i) Mechanisms of fatigue and autonomic dysfunction in Primary Biliary Cirrhosis
Primary Biliary Cirrhosis (PBC) is an autoimmune liver disease affecting up to 20,000 patients in the UK, mostly affecting females from middle age. The Newcastle PBC group, lead by Prof. David Jones, is internationally recognised for its work on the clinical expression of PBC.
Although, over many years, PBC can progress to end-stage liver disease which requires liver transplantation, loss of quality of life for patients in all stages is caused by profound, life-altering fatigue. The mechanism of this fatigue is not understood and there are no effective treatments. 50% of PBC patients suffer from fatigue, irrespective of the severity of their underlying liver disease. This fatigue often manifests itself as an inability to sustain physical exercise. It is unclear whether this fatigue arises from central nervous system control or whether it has a peripheral component.
To probe the potential mechanisms of non-sustenance of physical exercise, phosphorus spectroscopy of the exercising calf muscle has been performed to determine whether abnormal metabolic changes are observed in fatigued PBC patients. Phosphorus spectroscopy is able to non-invasively probe the concentrations of high-energy phosphates (PCr, inorganic phosphate, ATP and pH) as a time course in exercising muscle, allowing us to measure patterns of metabolite consumption, renewal and pH handling in the muscle.
Successive phosphorus spectra from exerciseing calf muscle showing the depletion and subsequent regeneration of phosphocreatine (PCr) and the accumulation and subsequent depletion of inorganic phosphate (Pi). A spectrum is collected every 10 seconds.
In addition, it has previously been observed that PBC patients with above median fatigue have a higher incidence of cardiac complications, which may implicate an abnormality in cardiac energetics, specifically the balance in content of phosphocreatine (PCr) and adenosine triphosphate (ATP). Non-invasive phosphorus-31 spectroscopy has been previously shown to detect abnormal cardiac metabolism in disease conditions where no anatomical defect is present. In this study, we will use it to determine whether a cardiac metabolic abnormality exists in patients with PBC.
(Left) Sample phosphorus spectrum from the heart of a control subject. (Right) Typical area of acquisition.
In addition, the project is also examining the basal ganglia structures of the brain to determine the presence of manganese and other trace elements in fatigued PBC patients. Earlier pilot work has suggested that there may be an association between manganese deposition in the globus pallidus (due to cholestasis) and patient fatigue.
This work seeks to confirm the observation on a larger cohort of patients and probe any further relationships between T1, T2 of basal ganglia structures with fatigue status of the patients.
Further information on this project can be obtained from Dr K.G.Hollingsworth
(ii) Assessing interventions in Non-Alcoholic Fatty Liver Disease (NAFLD)
Non-alcoholic fatty liver disease is now the most common cause of chronic liver disease world wide, affecting an estimated 20-30% of the British population. Although many patients with fatty liver can remain asymptomatic, they are at higher risk of developing liver fibrosis, portal hypertension, hepatocellular carcinoma and cirrhosis. Diagnosis and monitoring of the condition has traditionally been made by invasive liver biopsy.
Newcastle is well-known as a centre of excellence in the research into NAFLD within the research group of Prof. Chris Day.
Pharmaceutical treatment options are limited, meaning that lifestyle counselling is a key tool in remediating NAFLD. Counselled physical acitivity may offer key benefits over dieting in managing NAFLD given its influence over insulin sensitivity, lipid oxidation, liver metabolism and cytokine signalling. In order to create a convincing clinical case for these interventions, however, requires the demonstration of the effect of physical exercise on these mediators of NAFLD.
Non-invasive magnetic resonance techniques provide a unique tool in the study of NAFLD. Proton magnetic resonance spectroscopy can provide a rapid quantitative assessment of liver lipid content. Furthermore, its non-invasive nature means that longitudinal studies of liver fat change in response to interventions (such as physical exercise) are possible.
Typical proton spectra acquired from the liver (2 minutes) depicting liver water and fat content for a control subject (0.9% lipid) and a NAFLD patient (6.6% lipid).
It is also possible to create maps of liver content using magnetic resonance imaging in conditions where spatial discrimination of fat content is thought to be important.
Liver fat maps showing individuals with 4% fat conent and (right) with 9% fat content
Further information on this project can be obtained from Dr K.G.Hollingsworth.