Newcastle Magnetic Resonance Centre

Liver

Liver Research

Research

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:

Other liver projects

PBC

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 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.

Further information on this project can be obtained from Dr Kieren Hollingsworth.

NAFLD

Newcastle is well-known as a centre of excellence in the research into non-alcoholic fatty liver disease (NAFLD) within the research group of Prof Chris Day.

Non-alcoholic fatty liver disease (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. Further information on this project can be obtained from Dr Kieren Hollingsworth.

Biomarkers

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

The first of these involves monitoring oxidative stress in the liver, which is a process where reactive chemicals can be formed inside cells, with the potential to damage cellular components such as DNA, enzymes and membranes. The liver usually defends itself against oxidative stress, and central to this defence is cellular manufacture of antioxidants that neutralise the damage-causing reactive chemicals. We have developed a method of measuring the concentration and synthesis rate of glutathione, the principle hepatic antioxidant, in humans using 13C MR spectroscopy. Our studies have shown that both the concentration and synthesis rate of glutathione decrease in liver disease, which under some circumstances may facilitate the progression of liver disease. This novel biomarker has potential to provide an insight into the progression of liver disease in patients and into the biochemical impact of treatment regimes.

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.

Further information on these projects can be obtained from Dr Pete Thelwall.

Publications

2015

  • Gonzalez J, Fuchs C, Smith F, Thelwall P, Taylor R, Stevenson E, Trenell M, Cermak N, and van Loon L. Ingestion of Glucose or Sucrose Prevents Liver but not Muscle Glycogen Depletion During Prolonged Endurance-type Exercise in Trained Cyclists. Am J Physiol Endocrinol Metab 2015 Oct 20. doi:10.1152/ajpendo.00376.2015. PMID: 26350611.
  • Hallsworth K, Thoma C, Hollingsworth K G, Cassidy S, Anstee Q M, Day C P, Trenell M I. Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: A randomised controlled trial. Clin Sci (Lond). 2015 Dec;129(12):1097-105. doi: 10.1042/CS20150308. Epub 2015 Aug 11.
  • Jopson L, Newton JL, Palmer J, Trenell M, Blamire A, Howel D, Jones DE. RITPBC: B-Cell Depleting Therapy (Rituximab) as a Treatment for Fatigue in Primary Biliary Cirrhosis: study protocol for a randomised controlled trial. In press BMJ Open (2015).

2014

  • Hallsworth K, Thoma C, Moore S, Ploetz T, Anstee QM, Taylor R, Day CP, Trenell MI. Non-alcoholic fatty liver disease is associated with higher levels of objectively measured sedentary behaviour and lower levels of physical activity than matched healthy controls. Frontline Gastroenterol 2015; 6:44-51. doi:10.1136/flgastro-2014-100432.
  • Thelwall PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C, Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG. Hepatic Cholesteryl Ester Accumulation in Lysosomal Acid Lipase Deficiency: Non-invasive Identification and Treatment Monitoring by Magnetic Resonance. J Hepatol. 2013 Sep;59(3):543-9. doi: 10.1016/j.jhep.2013.04.016. Epub 2013 Apr 25. PubMed PMID: 23624251.
  • Hallsworth K, Hollingsworth KG, Thoma C, Jakovljevic D, Macgowan GA, Anstee QM, Taylor R, Day CP, Trenell MI. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J Hepatol. 2013 Apr;58(4):757-62. doi: 10.1016/j.jhep.2012.11.015. Epub 2012 Nov 22. PubMed PMID: 23178979.

2013

  • Thelwall PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C, Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG. Hepatic Cholesteryl Ester Accumulation in Lysosomal Acid Lipase Deficiency: Non-invasive Identification and Treatment Monitoring by Magnetic Resonance. J Hepatol. 2013 Sep;59(3):543-9. doi: 10.1016/j.jhep.2013.04.016. Epub 2013 Apr 25. PubMed PMID: 23624251.
  • Hallsworth K, Hollingsworth KG, Thoma C, Jakovljevic D, Macgowan GA, Anstee QM, Taylor R, Day CP, Trenell MI. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J Hepatol. 2013 Apr;58(4):757-62. doi: 10.1016/j.jhep.2012.11.015. Epub 2012 Nov 22. PubMed PMID: 23178979.

2012

  • Jones DEJ, Hollingsworth KG, Jakovljevic DG, Fattakhova G, Pairman J, Blamire AM, et al. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. European Journal of Clinical Investigation. 2012 Feb;42(2):186-94.
  • Smith FE, Mardini H, Record CO and Blamire AM. Reply to: "Ammonia and cerebral water. Importance of structural analysis of the brain in hepatic encephalopathy"', Journal of Hepatology, 2012, 56(2), pp. 506-507.

2011

  • Hollingsworth KG, Lim EL, Coombs A, Taylor R. Reproducibility of liver and pancreatic fat measurement in type 2 diabetes and normal subjects using the 3 point Dixon technique. Submitted 2011.
  • Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R ,Day CP, Trenell MI. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Hepatology Gut 2011;60:1278e1283. doi:10.1136/gut.2011.242073
  • Mardini H, Smith FE, Record C, Blamire AM. Magnetic resonance quantification of water and metabolites in the brain of cirrhotics following induced hyperammonaemia. J Hepatol. 2011; 54: 1154-1160

2010

  • Hollingsworth KG, Jones DEJ, Taylor R, Blamire AM, Newton JL. Impaired cardiovascular response to standing in chronic fatigue syndrome. European Journal of Clinical Investigation. 2010; 40(7):608-15.
  • Hollingsworth KG, Jones DEJ, Taylor R, Frith J, Blamire AM, Newton JL. Impaired cerebral autoregulation in primary biliary cirrhosis: implications for the pathogenesis of cognitive decline. Liver International. 2010; 30:878-85.
  • Hollingsworth KG, Newton JL, Robinson L, Taylor R, Blamire AM, Jones DE. Loss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in Primary Biliary Cirrhosis J Hepatol 2010;53:155-161
  • Jones D, Hollingsworth K, Taylor R, Blamire A, Newton J. Abnormalities in pH Handling by Peripheral Muscle and Potential Regulation by the Autonomic Nervous System in Chronic Fatigue Syndrome. Journal of Internal Medicine. 2010; Apr 267(4):394-401.
  • Jones DE, Hollingsworth KG, Fattakhova G, MacGowan GA, Taylor R, Blamire AM, et al. Impaired cardiovascular function in Primary Biliary Cirrhosis. Am J Physiol Gastrointest Liver Physiol 2010 May; Vol.298(5):PG764-773.
  • Newton J, Hollingsworth K, Taylor R, Blamire A, DE J. Loss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in primary biliary cirrhosis. J Hepatol 2010; 53(1):155-61.

2009

  • Hollingsworth KG, Jones DE, Aribisala BS, Thelwall PE, Taylor R, Newton JL, Blamire AM . Globus pallidus magnetization transfer ratio, T(1) and T(2) in primary biliary cirrhosis: relationship with disease stage and age. J Magn Reson Imaging. 2009 Apr;29(4):780-4.
  • Hollingsworth KG, Newton JL, Blamire A, Taylor R, Jones DE. Loss of capacity to recover from acidosis on repeat exercise is strongly associated with fatigue in primary biliary cirrhosis (PBC) Hepatology. 2009;50(4):1504.
  • Woodward JM, Priest AN, Hollingsworth KG, Lomas DJ. Clinical application of magnetic resonance spectroscopy of the liver in patients receiving long-term parenteral nutrition. J Parenter Enteral Nutr. 2009; 33:669-76.

2008

  • Hollingsworth KG, Newton JL, Taylor R, McDonald C, Palmer JM, Blamire AM, et al. Pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis. Clin Gastroenterol Hepatol. 2008 Sep;6(9):1041-8.
  • Newton JL, Hollingsworth KG, Taylor R, El-Sharkawy AM, Khan ZU, Pearce R, et al. Cognitive impairment in primary biliary cirrhosis: symptom impact and potential etiology. Hepatology. 2008 Aug;48(2):541-9.
  • van der Poorten D, Milner K, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449-57.