Drug-induced Liver Injury, Non-alcoholic Fatty Liver Disease & Stratifying patients with Chronic Liver Disease

Drug-induced Liver Injury (DILI): Considering the fact that animal toxicological investigations have singularly failed to elucidate mechanisms underlying idiosyncratic DILI, we have developed well characterised cohorts of cases of DILI and controls to investigate genetic, epigentic and environmental factors that influence the development of this rare, yet serious adverse reactions to medications and to evaluate markers that assist in the detection, diagnosis of DILI and prevent its serious consequences.

Non-alcoholic Fatty Liver Disease (NAFLD): Host genetic and life style factors influence the development and progression of NAFLD. We investigate the metabolic factors and pathophysiological processes contributing to the development of NAFLD. We evaluate the effects of interventions in NAFLD and mechanisms underlying these using our prospective deeply phenotyped cohort of patients with NAFLD.

Stratifying patients with Chronic Liver Disease: We develop, evaluate and validate novel techniques and tools to assist stratification of chronic liver diseases, monitor their progress and assess efficacy of interventions.

Current projects:

  • Prospective European DILI Cohort (Pro Euro DILIC): Prof Aithal is the joint Chief Investigator for this study supported by European association for the Study of Liver (EASL).
  • Investigation of genetic and lifestyle factors determining the susceptibility to insulin resistance and NAFLD in a South Indian Cohort. This study in collaboration with Population Health and Research Institute, Trevandrum, India will complete enrollment soon.
  • We are evaluating the genetic factors and the pathogenesis of NAFLD in a large three-generation family with fatty liver and a particularly high rate of conversion to cirrhosis and hepatocellular carcinoma (HCC). This could lead to novel therapeutic strategies for prevention and treatment of NAFLD as well as provide insight into the molecular mechanisms behind the development of HCC.
  • Quantitative Magnetic Resonance Imaging: In collaboration with Sir Peter Mansfield Imaging Centre (SPMIC) we are developing novel techniques of estimating portal hypertension and
  • gut permeability with an eventual aim of effectively stratifying patients with chronic liver disease for appropriate interventions and assess the efficacy of these interventions.
  • MRC Confidence in Concept Project: Developing a new Magnetic Resonance Spectroscopy technique to non-invasively measure hepatic oxidative stress in-vivo as a biomarker of liver health.

Potential for collaborative projects:

  • MRC/EPSRC Nottingham Molecular Pathology Node (NMPN): Prof Aithal is the Deputy Director of NMPN. This project will develop a robust clinically applicable algorithm that estimates the degree of histopathological changes in NAFLD patients integrating existing and novel biomarkers derived from clinical, serum, imaging and molecular pathology based parameters. We have an opportunity to develop novel biomarkers in a deeply phenotyped cohort of patients with NAFLD and linked biorepository.
  • Prof Aithal has successfully conducted randomised controlled trials (RCT) in non-alcoholic steatohepatitis (NASH); he lead the first study demonstrating the efficacy of pioglitazone in NASH and was a co-investigator in another RCT of liraglutide in NASH. His research group with expertise in metabolic physiology, cell biology, diagnostics including advanced imaging can evaluate the mechanisms of action and efficasy of novel interventions. NIHR Nottingham Biomedical Research Unit (NDD BRU) has the infrastructure and experience of delivering early phase studies of novel therapy for NAFLD.
  • Pro Euro DILI Cohort will be co-ordinated from NIHR NDD BRU and will act as the central biorepository. This will enroll prospectively deeply phenotyped cases of acute DILI and drug-exposed control groups; this will provide the richest resource for biomarker discovery. It will also provide an opportunity to evaluate novel interventions to improve outcomes from acute DILI.

Key team members (PIs):

Drug-induced Liver Injury: Prof Guruprasad Aithal, Dr Jane Grove, Dr Andrew Bennett and Dr Nick Hannan

Non-alcoholic Fatty Liver Disease: Prof Guruprasad Aithal, Prof Ian Macdonald, Dr Francis Stephens, Dr Iskandar Idris and Dr Jane Grove

Startifying patients with chronic liver disease: Prof Guruprasad Aithal, Prof Penny Gowland, Dr Susan Francis, Dr Neil Guha, Dr Philip Kaye

Administrative Contact:

Maria Matthews

Tel: +44 (0) 115 9249 924 ext 63822

Email: Maria.Matthews@nottingham.ac.uk