Consortium

Institute of Preventive Medicine

fatty liver inhibition of progression

The FLIP consortium has been built around practising clinical hepatologists, basic scientists and 2 industrial partners with an established track record, and focus on research into the underlying mechanisms and management of patients with NAFLD.

Understanding and preventing the progression of liver disease in Non Alcoholic Fatty Liver Disease (NAFLD)

Acknowledgement
The FLIP project is supported by the European Commission through the Seventh Framework Programme for Research and Development and has been running since January 1st 2010 (duration 36 months).

fatty liver inhibition of progression

Project Coordinator: Assistance Publique - Hpitaux de Paris (APHP), Prof. Vlad Ratziu, +33 1 42 16 10 20, vratziu@teaser.fr With the support of: ALMA Consulting Group SAS, Tania Langon, +33 4 72 35 88 48, tlangon@almacg.com www.flip-fp7.eu
A European Medium-Scale Project supported through the Seventh Framework Programme for Research and Technological Development.

fatty liver inhibition of progression

What is NAFLD?
NAFLD encompasses a spectrum of liver disease associated with insulin resistance, diabetes and obesity. It ranges from excess fat in the liver (steatosis), to fat in combination with inflammation and liver cell injury (steatohepatitis), to cirrhosis and its complications, liver cancer in particular. Cirrhosis describes the fibrosis or scarring that occurs as part of a wound healing response to non alcoholic steatohepatitis, which is commonly called NASH.

Objectives
The aim of the FLIP consortium (Fatty Liver Inhibition of Progression) is to understand and prevent the progression of NAFLD to its more severe forms. The main outcomes of FLIP will be: New insights into its progression, particularly in terms of identifying the initiating mechanisms and patients at risk. Developing innovative diagnostic methods adapted for large-scale screening and prognostic evaluation. Characterising the key pathways and molecular targets amenable to pharmacological therapy, and finally, the improvement of implementation of lifestyle changes.
NAFLD Inflammation (hepatitis)
presence of inflammatory cells in the liver change in liver structure slowed blood circulation hepatocyte necrosis on-going inflammation leads to fibrosis

Fibrosis
scarring of the liver due to excessive accumulation of fibrotic matrix and related to continuous liver damage, inflammation and hepatocyte death extent of damage can be evaluated through liver biopsy or selecting non-invasive procedures distortion of hepatic architecture with incipient portal hypertension

Chronic liver disease

End-stage liver disease

Cirrhosis
liver becomes permanently scarred clinical portal hypertension develops liver function is impaired

Isolated steatosis (fatty liver without inflammation or scarring)

Steatohepatitis with MalloryDenk bodies and inflammation

NASH with advanced fibrosis

NASH cirrhosis

Hepatic insufficiency/ hepatic failure Hepatocellular carcinoma (HCC)

Context / Impact
NAFLD is a major health problem and rapidly becoming one the most common liver diseases worldwide. The prevalence of NAFLD in the general population of Western countries is 20-30%. The prevalence of NAFLD and NASH is increasing in overweight children and adults but also in insulin-resistant individuals of normal weight. Due to the rapidly progressing epidemics of obesity and diabetes, a large segment of the population is at risk for NAFLD. Particulary worrisome is the emergence of NAFLD/NASH with significant fibrotic disease in developing countries, even in patients of normal weight or who are underweight. Overall, FLIP will study mechanisms of progression and suggest preventive and therapeutic strategies. The main deliverables are: Creation of a prospective European cohort of patients with standardised inclusion criteria and histologically proven NAFLD/NASH  Creation of a prospective European observatory of hepatocellular carcinoma in NASH Identification of novel epidemiological determinants for NAFLD in adolescence and adulthood Identification of clinical correlates and mechanisms of progression in NAFLD (spanning all the steps of the disease and answering key issues dealing with the interplay of metabolic, inflammatory and fibrotic factors in the initiation and perpetuation of liver injury) V  alidation of improved diagnostic and prognostic markers for NAFLD  Validation of consensual histological classification of NAFLD/NASH Improved implementation of preventative strategies in NAFLD

Methodology and workflow

SP1 NAFLD cohort & database; histological definition SP8 Results dissemination exploitation

SP2 Epidemiology of NAFLD

SP7 Innovative diagnostic and pronostic markers SP6 Improved implementation of preventive strategies

Diagnosis and Prognosis

Currently the only way of diagnosing NASH is by liver biopsy, an invasive procedure, unsuitable for the screening of at-risk individuals. The development of non-invasive strategies for diagnosis and staging is therefore a priority for the optimal management of this disease, as is the validation of consensual pathological classification. The further characterization of severe complications of NASH (cirrhosis, hepatocellular carcinoma) and of the interaction with cardiovascular outcomes is urgently needed.

SP3 Metabolic factors

SP5 Fibrosis factors & carcinogenesis

SP4 Inflammatory factors Clinical correlates and mechanism of progression in NAFLD SP9 Project management

In the long term, FLIP aims to lay the foundations for the future of NAFLD research in Europe and create a European Collaborative Research Network on NAFLD.