Liver Research

Primary Biliary Cholangitis (PBC)

PBC is an autoimmune liver disease affecting up to 20,000 patients in the UK, mostly affecting females from middle age. The 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.

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.

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.

Non-alcoholic fatty liver disease (NAFLD)

NAFLD 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.

Pharmaceutical treatment options are limited, meaning that lifestyle counselling is a key tool in remediating NAFLD. Counselled physical activity may offer key benefits over dieting in managing NAFLD given its influence over insulin sensitivity, lipid oxidation, liver metabolism and cytokine signalling. 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.

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. 

Biomarkers

We have developed several new scan methods that allow probe biochemical pathways central to the development of liver disease.

In a parallel study we have developed new methods to diagnose and monitor the progression of a genetic disease, Cholesterol Ester Storage Disease (CESD). This condition causes progressive liver damage due to the body’s inability to break down cholesterol esters, resulting in fat accumulation in hepatic tissues that disrupts cellular. Until recently the only treatment for CESD was liver transplant, but novel enzyme replacement therapies that provide functional lysosomal acid lipase enzyme are currently entering clinical trials. We have developed methods to measure liver cholesterol ester content by a non-invasive MRI scan, allowing disease progression and treatment efficacy to be monitored without the need for invasive tissue biopsy.