Non-alcoholic Fatty Liver Disease Group

One significant interest of our group is a risk-stratification and economic analysis for the development of a NAFLD referral/management strategy pathway in the diabetic population in three different healthcare systems: the UK, Sicily and Egypt.

Why it is important

We will determine the frequency and severity of fatty liver disease in patients with type 2 diabetes in Cairo, Sicily and London. Introducing appropriate screening in this high-risk population will diagnose advanced liver disease earlier and reduce progression rates to end-stage liver disease and, subsequently, number of liver and heart related-events, and requirement for liver transplantation. Finally, a correct risk-stratification will allow for the development of a fatty liver screening and referral/management strategy pathway tailored for the healthcare system of each country.

The Egyptian cohort will be compared with the Italian and London based population with regards to phenotype, diet, clinical parameters and clinical events (liver and non-liver related) and metabolic profile, giving us an insight on the environmental, genetic and microbiome factors involved in the pathogenesis of NAFLD.

How it can benefit patients

This is critical, as still the exact pathogenesis of NAFLD remains poorly understood and is thought to involve a combination of genetic and environmental influences including genetic susceptibility, immunological pathways, diet, exercise, and the gut microbiota. It is expected that the research data and mainly the comparison of these cohorts -patients with diabetes and NAFLD, patients with diabetes without NAFLD, could identify metabolites and new protective microbial strategies (pre- or pro- biotics) which could lead to new interventions for Non Alcoholic Fatty Liver Disease. In the future, this knowledge might be exploitable for ‘personalised medicine’ approaches, by allowing us to try and better match patients starting treatment to a therapy that we can be confident will work well for them.

Another major interest of our group is applying artificial intelligence in the interpretation of liver biopsies. The software we are developing is based on a deep-learning approach which means that it is designed to refine its knowledge and become more accurate automatically as it is used.

Why it is important

To date, there is no single blood test or imaging technique which can establish a definite diagnosis of NASH or assess disease severity (what is the degree of the scarring) and there is no approved drug treatment. Liver biopsy, although invasive, remains the mainstay of diagnosis and assessment of disease severity both of which are needed for clinical plan, appropriate treatment, and inclusion to clinical trials in the case of NAFLD/NASH. Currently, biopsies are assessed by liver pathologists in a very subjective way and in a pattern established many years ago and currently outdated. We have shown that this variability in reporting between pathologists has a detrimental impact on individual patients as it impacts on clinical decision making. It also affects the development of non-invasive markers of disease severity (for example simple blood tests) that could, potentially, replace liver biopsy in the future.

How it can benefit patients

When complete, this work will lead to a universal, objective, standardised interpretation of liver biopsies and change the landscape in liver pathology: this will improve clinical outcomes, reduce screen failure rates in clinical trials, and develop more valid non-invasive markers of disease activity.

We are also running three clinical trials, translating our research outcomes to direct care for our patients:

1. SINERGY-NASH
2. REGENERATE-747-303
3. REVERSE 747-304
4. MAESTRO
5. ESSENCE
6. NAFLD Bioresource
7. Oxford Wellcome TrUst-NAFLD

Other projects currently active in the NAFLD research group are:

1. The role of microbiome and gut permeability in modulating sarcopenia in diabetic patients with Non-alcoholic fatty liver disease: a cross-sectional multicentre study with Dr Giordano Sigon and Professor Anna Fracanzani
2. A proof-of-concept trial of digoxin use as senolytic in patients with NAFLD and inflammation on liver biopsy in collaboration with Professor Jesus Gil.
3. An open label single centre phase 2 trial of Faecal Microbial Transplantation in patients with NASH in collaboration with Professor Mark Thursz, Professor Marc Dumas and Dr Benjamin Mullish.
4. An open-label randomized control trial for diabetic patients with NAFLD comparing dietary advice and feedback informed by metabolic profiling to standard of care aiming to improve dietary habits during a 12-week period in collaboration with Professor Gary Frost and Dr Isabel Garcia-Perez.
5. Defining the Lipidome of Non-alcoholic Steatohepatitis (NASH) by Dan Wang
6. Lipid metabolism in MAFLD-associated HCC by Dr Jian Huang
7. Developing the glucagon-alanine index test to improve the health of people with non-alcoholic fatty liver disease by Professor Tricia Tan
8. Investigation of NAFLD-associated epigenetic dysregulation by Dr Ines Cebola
9. Identification of NASH contributing factors with single-cell omics by Dr Ines Cebola
10. Discovery of NAFLD gene regulatory networks, The Welcome Trust, Sir Henry Dale Fellowship by Dr Ines Cebola

Funders

European association for the study of the liver (EASL)
NIHR Academic Clinical Lectureship (CL-2019-21-002)
NIHR Imperial Biomedical research centre (BRC)

Related centres

• National Phenome Centre (NPC)
• NIHR Imperial Biomedical Research Centre (BRC)

Internal

• Prof Robert Goldin, Department of Metabolism, Digestion and Reproduction, Imperial
• Prof Julian Marchesi, Department of Metabolism, Digestion and Reproduction, Imperial
• Prof Marc-Emmanuel Dumas, Department of Metabolism, Digestion and Reproduction, Imperial
• Prof Gary Frost, Department of Metabolism, Digestion and Reproduction, Imperial
• Prof Waljit Dhillo, Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial
• Prof Tricia Tan, Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial
• Prof Julian Griffin, Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial
• Dr Zoe Hall, Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial
• Dr Ines Cebola, Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial
• Dr Rohini Sharma, Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial

External

• Prof Emmanouil Tsochatzis, Institute for Liver and Digestive Health, University College of London
• Prof Eleanor Barnes, Faculty of Medicine, University of Oxford
• Dr Christos Triantos, Gastroenterology, Faculty of Medicine, University of Patras
• Dr Nikolas Giannakeas and Dr Alexandros Tsipouras, Department of Informatics and Telecommunications, University of Western Macedonia.
• Dr Markos Tsipouras, Department of Engineering Informatics and Telecommunications, University of Western Macedonia.
• Prof Anna Fracanzani, Faculty of Medicine, University of Milan
• Prof Salvatore Petta, Gastroenterology, Faculty of Medicine, University of Palermo

Forlano R, Mullish BH, Roberts LA, Thursz MR, Manousou Pet al., 2022, The intestinal barrier and its dysfunction in patients with metabolic diseases and non-alcoholic fatty liver disease, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067 (https://pubmed.ncbi.nlm.nih.gov/35054847/)

Forlano R, Harlow C, Mullish BH, Thursz MR, Manousou P, Yee Met al., 2021, Binge-eating disorder is associated with an unfavourable body mass composition in patients with Non-alcoholic fatty liver disease, International Journal of Eating Disorders, Vol: 54, Pages: 2025-2030, ISSN: 0276-3478 (https://pubmed.ncbi.nlm.nih.gov/34272900/)

Forlano R, Mullish BH, Maurice JB, Thursz MR, Goldin RD, Manousou P, 2021, NAFLD: time to apply quantitation in liver biopsies as endpoints in clinical trials, Journal of Hepatology, Vol: 74, Pages: 241-242, ISSN: 0168-8278 (https://pubmed.ncbi.nlm.nih.gov/33012546/)

Forlano R, Mullish BH, Mukherjee SK, Nathwani R, Harlow C, Crook P, Judge R, Soubieres A, Middleton P, Daunt A, Perez-Guzman P, Selvapatt N, Lemoine M, Dhar A, Thursz MR, Nayagam S, Manousou Pet al., 2020, In-hospital mortality is associated with inflammatory response in NAFLD patients admitted for COVID-19, PLoS One, Vol: 15, ISSN: 1932-6203 (https://pubmed.ncbi.nlm.nih.gov/33031439/)

Kim JU, Majid A, Judge R, Crook P, Nathwani R, Selvapatt N, Lovendoski J, Manousou P, Thursz M, Dhar A, Lewis H, Vergis N, Lemoine Met al., 2020, Effect of COVID-19 lockdown on alcohol consumption in patients with pre-existing alcohol use disorder, LANCET GASTROENTEROLOGY & HEPATOLOGY, Vol: 5, Pages: 886-+

Forlano R, Mullish BH, Giannakeas N, Maurice JB, Angkathunyakul N, Lloyd J, Tzallas AT, Tsipouras M, Yee M, Thursz MR, Goldin RD, Manousou Pet al., 2020, High-throughput, machine learning-based quantification of steatosis, inflammation, ballooning, and fibrosis in biopsies from patients with nonalcoholic fatty liver disease, Clinical Gastroenterology and Hepatology, Vol: 18, Pages: 2081-2090.e9, ISSN: 1542-3565 (https://pubmed.ncbi.nlm.nih.gov/31887451/)

Hanley B, Naresh KN, Roufosse C, Nicholson AG, Weir J, Cooke GS, Thursz M, Manousou P, Corbett R, Goldin R, Al-Sarraj S, Abdolrasouli A, Swann OC, Baillon L, Penn R, Barclay WS, Viola P, Osborn Met al., 2020, Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study, The Lancet Microbe, Vol: 1, Pages: e245-e253, ISSN: 2666-5247 (https://pubmed.ncbi.nlm.nih.gov/32844161/)

Abeles RD, Mullish BH, Forlano R, Kimhofer T, Adler M, Tzallas A, Giannakeas N, Yee M, Mayet J, Goldin RD, Thursz MR, Manousou Pet al., 2019, Derivation and validation of a cardiovascular risk score for prediction of major acute cardiovascular events in non-alcoholic fatty liver disease; the importance of an elevated mean platelet volume, Alimentary Pharmacology and Therapeutics, Vol: 49, Pages: 1077-1085, ISSN: 0269-2813 (https://pubmed.ncbi.nlm.nih.gov/30836450/)