First European NAFLD-NASH Summit European Parliament, Brussels, May 31 st 2017 NAFLD/NASH : an expanding burden on liver health Vlad Ratziu, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France
Diet Lifestyle Heritability/ genetic Comorbid conditions (metab sd, diabetes, OSA) Non-Alcoholic Fatty Liver Disease (NAFLD) Steatosis in >5% of hepatocytes Microbiota Non-Alcoholic Steatohepatitis (NASH) Steatosis Lobular Inflammation Hepatocellular ballooning Non-Alcoholic Fatty Liver (NAFL) Steatosis in >5% of hepatocytes No or minimal inflammation FIBROSIS early (F0, F1) advanced (F2, F3) cirrhosis (F4) cirrhosis decompensation encephalopathy ESLD (OLT) HCC neurocognitive disorders - QOL
Portal fibrosis peri sinusoidal fibrosis Bridging fibrosis cirrhosis
Obesity : magnitude of the problem 2 Billion adults overweight (39%) 600 Million adults obese (13%) USA: 2/3 overweight or obese
Global prevalence of NAFLD : 25% Trends 2000-2005: 20%; 2005-2010: 24%; 2011-2015: 27%
NAFLD Secondary Alcohol Drugs (amiodarone, metothrexate, tamoxifen, corticosteroids) A/hypo betalipoprotéinémia Chronic HCV (genotype 3) Wilson disease Industrial toxins Lipodystrophies Cholesteryl ester storage disease Microvesicular steatosis PRIMARY Metabolic Risk Factors
Causes of Cirrhosis (US) Multiethnic Cohort, Medical Claims, Medicare claims 1999-2012 10% NAFLD 29% NAFLD ALD HCV Crypto HBV Other Setiawan, Hepatology 2016
NASH as an indication for liver Data from UNOS Registry 2004-2013 transplantation NASH : second cause of LT waitlist registrants NASH : less likely to undergo LT NASH : less likely to survive for 90 days on the waiting list Wong, Gastroenterology 2015
Prevalence of NAFLD and NAFLD fibrosis in the general Dutch population (>45 yrs) N= 3041 indiv, general pop, >45 yrs 35.5 % NAFLD 27 % Alcohol, drugs, viruses 2.3 % NAFLD fibrosis Koehler, Hepatology 2016
Factors associated with Fibrosis in the general Dutch population older than 45 yrs Age Diabetes 34%-10% Male sex 62%-44% Steatosis 59%-34% Smoking 78%-64% LSM >8 kpa Metab Sd Alcohol NO! Koehler, Hepatology 2016
NAFLD is an increasing cause of HCC in Northern England Over the past decade 35% ALD: 28% NAFLD: 22% No CLD: 20% Dyson, J Hepatol 2013
NAFLD : an underrecognized disease 100 80 60 40 20 0 60.6% 39.4% recognition of ALT increase 21.5% diagnosis of NAFLD/NASH 15% lifestyle modifications 10.5% referral specialist evaluation NO NAFLD CARE Only the magnitude and proportion of ALT elevation were predictive of receiving NAFLD care Blais, Am J Gastroenterol 2014
Routine, non-invasive assessment of hepatic fibrosis SERUM MARKERS TRANSIENT ELASTOMETRY Fibrometer biopredictive.com Biols.fr
MRE elastography Loomba, Hepatology 2014
NASH : reduced survival Survival vs. the general population Liver-related mortality STEATOSIS NASH Cardiovascular mortality Same survival as the general population Cirrhosis : an independent risk factor of death Hepatocellular carcinoma Matteoni, Gastro 1999, Adams, Gastro 2005, Ekstedt, Hepatol 2006, Ong, J Hepatol 2008, Dunn AJG 2008, Sorderberg, Hepatology 2010, Dyson J Hepatol 2014
NAFLD Both consequence and catalyzer of the metabolic syndrome? Hypertension Cardiovascular Prevalence essential HTN Incident diabetes Insulin requirements NAFLD Diabetes Endothelial & coronary dysfunction Carotid plaques Impaired ventricular fct and metabolism CV events
Work-up in patients with NAFLD: a multiorgan approach NAFLD Extrahepatic comorbidities? Liver condition Type 2 diabetes Sleep apnea Hypertension, arterial Dyslipidemia Cofactors of fibrosis Pathological form Stage Prognosis
First records of CLDs in Scotland by diabetes status Retrospective population-based cohort Scottish Diabetes Register & National hospital cancer and death records 2004-2013; 40-89 years; 26 M Pt/years of F/u 97% mono diagnosis of CLD #2 #1 #1 #2 Wild, J Hepatol 2016
Impact of NAFLD on health-care utilization and cost in a general population Cohort Study of Health in Pomerania, 1997-2006 4310 patients at baseline 5 year follow-up examination in 3300 subjects 4 categories : US +/-, ALT N/abN 14% US-, ALT N 16% 10% 60% US-, ALT abn US+, ALT N US+, ALT abn Baumeister, Gastroenterology 2010
40 Levels of health-care utilization and costs US +, ALT abn vs. US neg, ALT N 35 30 % higher cost 25 20 15 10 US +, ALT abn 5 0 Adjusted on sex, age, income, education, smoking, physical activity, BMI, waist circumf Baumeister, Gastroenterology 2010
Diet Exercise
Weight loss pyramid Weight Loss 10% 1 Fibrosis (45%) Patients achieving: <10% in 1 year 1 Weight Loss 7% 1 NASH Resolution (64 90%) * 18% in 1 year 1 Weight Loss 5% 1-3 Ballooning / inflammation (41 100%) * 30% in 1 year 1 Weight Loss 3% 1-4 Steatosis (35 100%) * *Depending on degree of weight loss 1 Vilar-Gomez E, et al. Gastroenterology. 2015;149:367-78. 2 Promrat K, et al. Hepatology. 2010;51:121-9 3 Harrison SA, et al. Hepatology. 2009;49:80-6. 4 Wong VW, et al. J Hepatol. 2013;59:536-42 Slide courtesy of S. Harrison 22
Exercise Diet Drugs
Late phase RCTs in NASH Completed Phase 2b trials: FLINT: obeticholic acid vs. Placebo (Lancet 2015) GOLDEN: elafibranor vs placebo (Gastroenterology 2016) CENTAUR (Year 1): cenicriviroc vs placebo (submitted) Current Phase 3 trials (registrational): REGENERATE (obeticholic acid) RESOLVE-IT (elafibranor) STELLAR 1 and 2 (selonsertib) STELLARIS (cenicriviroc)
EASL EASD - EASO V Ratziu May31st 2017
Fatty Liver: Inhibition of Progression HEALTH-F2-2009-241762 Subprogram Area: Prevention and treatment of non-alcoholic fatty liver disease (NAFLD) Contract type: Small or medium-scale focused research project
EPoS The EPoS project has received funding from the European Union s Horizon 2020 research and innovation programme under grant agreement No. 634413 www.epos-nafld.eu 2 nd SC Meeting, 26-27/1/16 27
Investigative Medicines Initiative 2: Call 9 (2016) LITMUS Liver Investigation: Testing Marker Utility in Steatohepatitis 2 nd SC Meeting, 26-27/1/16