Natural History of Alcoholic Liver Disease: Role of Hepatitis C, Environmental, Genetic Factors and Gender Differences

Transcription

1 Natural History of Alcoholic Liver Disease: Role of Hepatitis C, Environmental, Genetic Factors and Gender Differences AISF Monothematic Conference, Rome October 5th, 2017 Luca Valenti Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy Internal Medicine, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

2 Luca Valenti, prof. Associato di Medicina Interna Università degli Studi di Milano Il sottoscritto dichiara di non aver avuto/di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene/contiene discussione di farmaci in studio o ad uso off-label

3 Outline Overview and the role of steatosis Traditional risk factors Impact on chronic hepatitis C A genetic point of view of the disease

4 Outline Overview and the role of steatosis Traditional risk factors Impact on chronic hepatitis C A genetic point of view of the disease

5 Cause specific increase in mortality in alcoholic fatty liver disease - AFLD 59.9 General population AFLD NAFLD Overall Liver disease CVD non-gi cancer Infection 0 Jepsen P, Hepato-Gastroenterology 2003

6 Temporal trends, USA HCV ALD NAFLD Goldberg, Gastroenterology 2017

7 Hepatic ethanol metabolism 1A- Alcohol dehydrogenase (ADH) Ethanol NAD ADH NADH Acetaldehyde 1B - MEOS (P 450 ) - inducible Ethanol + O 2 2- Aldehyde dehydrogenase NADPH NADP MEOS CYP2E1 Acetaldehyde +H 2 O+ ROS Acetaldehyde NAD NADH Acetate

8 Pathogenesis of alcoholic steatosis ALCOHOL Mitochondrial damage AMPK NADH FFAs flux ROS acetaldehyde lipogenesis SREBP1c VLDL secretion beta-oxidation Acetate

9 Natural history of alcoholic fatty liver Alcohol use with nutritionally complete diet Normal 90-95% Steatosis 2-3% / year Steatohepatitis 10-35% Fibrosis Cirrhosis 3-10% HCC Abstinence Resolves over 30 days RISK FACTORS: Gender: female Alcohol use: daily or continued heavy Histology: megamitochondria, severe or micro steatosis, inflammation Comorbidities: obesity, hemochromatosis, chronic viral infections

10 Natural history of alcoholic hepatitis All were abstinent Normal 10-46% Alcoholic hepatitis 87 pts, f-up to 9 yrs 35-38% Cirrhosis 19-52% Steatosis Galambos, Gastroenterology 1972 Pares, J Hepatol 1986

11 T cells IL-12 NKT NK Th1 cytokines TGF- B cells CYP2E1 TNF-R1 MHC HSCs C3a/C5a Kupffer cells TLR-4 ROS IFN- IL-12 TNF IL-10 IL-6 IL-1 MCP-1 Resistin TNF IL-6 Adiponectin Alcohol SIBO LPS Increased intestinal permeability Fatty acids Valenti, Sem Immunopathol 2009

12 Outline Overview and the role of steatosis Traditional risk factors Impact on chronic hepatitis C A genetic point of view of the disease

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14 Relationship between the amount of alcohol consumed and the probability to develop ALD N=2,202 OR (95% ci) ALD Cirrhosis Ref NS (4-14) (9-43) (5-43) (16-82) Ref NS (4-34) (8-79) (17-169) (20-193) Bellentani, Gut 1997; Corrao Prev Med 2004

15 Lower threshold in females Sorensen, Hepatology 1996

16 Association between Binge Drinking and risk of decompensated cirrhosis Adjusted for sex and alcohol intake (Per year) Aberg, Liv Int 2017

17 Gender and alcohol Females develop ALD at lower intake Explanation: Reduced volume of distribution Reduced gastric ADH expression Estrogen sensitizes Kupffer cells to LPS Marshall 1983, Seitz Gut 1993, Thurman 1999, Bannerjee 2006

18 Mortality for alcoholic liver disease in Europe in 2005 (WHO 2010) MEN WOMEN Blachier, J Hepatol 2013

19 Excessive alcohol intake & obesity: synergistic effect on fatty liver Relative risk of steatosis in the study groups Bellentani, Ann Intern Med 2000 Study N Results Naveau 1604 Overweight >10y increases steatosis and cirrhosis Raynard 268 BMI associated with fibrosis stage >F2

20 Protective effect of coffee intake on risk of cirrhosis (n=125,580) Klatsky, Arch Intern Med 2006

21 Outline Overview and the role of steatosis Traditional risk factors Impact on chronic hepatitis C A genetic point of view of the disease

22 Alcohol and HCV: effect of alcohol excess Author Study design N Results Serfaty, 1997 Case-control g/d increases risk of cirrhosis Wiley, 1998 Case-control 176 Increases cirrhosis and decompensation Pessione, 1998 Cross sectional 233 Increases replication and fibrosis progression Corrao, 1998 Case-control 702 Lifetime consumption correlates w/ cirrhosis Niederau, 1998 Cohort study 838 Alcohol RF for cirrhosis Bellentani, 1999 Cross sectional 6917 >30 g/d favors cirrhosis and HCC Thomas, 2000 Cohort study 1667 >260g/w favors cirrhosis Harris, 2001 Cohort study 1030 Increases cirrhosis risk 4-fold Monto, 2004 Cross sectional 800 >50g/d increases fibrosis and cirrhosis Boccato, 2006 Prospective study 106 >40g/d increases cirrhosis risk 4-fold Lange, 2012 Cross sectional 312 >40g/day for 5y increases fibrosis Kirk, 2013 Cross sectional 1176 Alcohol use favors fibrosis in HIV-IVDU Minisini, 2013 Cohort study 182 Genetic predisposition (DRD4) associated with fibrosis

23 Synergy between alcohol and HCV in determining liver disease Punzalan, J Vir Hep 2016

24 Prevalence of alcohol use disorders in chronic hepatitis C in France, : A nationwide retrospective cohort study (N=97,347) 29% Schwarzinger, J Hepatol 2017

25 Risk of liver transplantation or premature death by alcohol use disorders and age in patients discharged with chronic HCV infection Schwarzinger, J Hepatol 2017

26 Population attributable risk (PAR) of liver-related complications in patients discharged with chronic HCV infection Schwarzinger, J Hepatol 2017

27 Factors involved in the progression of ALD Host genetics Alcohol Comorbidity Gender Iron storage Ethnicity Genetic variants Cirrhosis Metabolic syndrome Chronic viral hepatitis Nutrition Modified from Stickel, Gut 2011

28 Outline Overview and the role of steatosis Traditional risk factors Impact on chronic hepatitis C A genetic point of view of the disease

29 The genetic determinants of alcoholic cirrhosis Buch, Stickel & Trepo, Nat Genet 2015

30 PNPLA3 I148M and progressive fibrosis ALD RISK Alcoholic Liver Disease Odds Ratio Advanced fibrosis Chronic HCV Hepatitis Odds Ratio Advanced fibrosis I/M vs. I/I Tian, Nat Genet 2009 Stickel, Hepatology 2010 Seth, Hepatology 2010 Trepo, Hepatology 2011 Burza, Liv Int 2013 Valenti, Hepatology 2011 Muller, J Hepatol 2011 Trepo, Hepatology 2011 Valenti, AP&T 2012 Patin, Gastroenterology 2012 M/M vs. I/I Allelic OR Allelic OR M 148M see also meta-analysis: Salameh, Am J Gastroenterol 2015

31 Modulation of the effect of the PNPLA3 I148M variant on steatosis and cirrhosis by alcohol intake in CHC 3 Valenti, J Hepatol 2011

32 Alcohol and obesity favor lipid droplets accumulation in hepatocytes ALCOHOL Obesity Lipid droplets HFC: 0-5% Extracellular space FFAs PNPLA3 148I TM6SF2 167E Tg Nascent VLDL VLDL secretion Endoplasmic Reticulum Early Golgi Dongiovanni, BMC Research International, 2015

33 Impaired lipid droplets remodeling causes steatohepatitis in PNPLA3 I148M carriers ALCOHOL Obesity HFC: 6% PNPLA3 148M Extracellular space ATGL (PNPLA2) FFAs Lipid droplets TM6SF2 167E Tg Nascent VLDL VLDL secretion Endoplasmic Reticulum Early Golgi Romeo, Nat Genet 2008, He, J Biol Chem 2010; Ruhanen, J Lipid Res 2014; Dongiovanni, World J Gastroentorol 2013; Dongiovanni, Hepatology 2014; Donati, Hepatology 2016; Basuray, Hepatology 2017

34 PNPLA3 has retynil-esterase activity in HSCs and the I148M variant is a loss of function Retinyl-palmitate PNPLA3 148M Insulin TGF- Palmitic acid Retinol Retinal Retinoic acid ADH ALDH ETOH MMP2-TIMP1/2 CCL5 GMCSF Inihibition of lipogenesis Regeneration Differentiation

35 TM6SF2 is involved in lipidation of VLDL and secretion of lipids from hepatocytes Obesity Insulin resistance Lipid droplets HFC: 0-5% Extracellular space FFAs PNPLA3 148I TM6SF2 167E Tg Nascent VLDL VLDL secretion Endoplasmic Reticulum Early Golgi Dongiovanni, BMC Research International, 2015; Smagris, J Biol Chem 2016

36 Impaired VLDL secretion in E167K TM6SF2 carriers causes fatty liver Obesity Insulin resistance Lipid droplets Extracellular space FFAs PNPLA3 148I HFC: 6% TM6SF2 167K Nascent VLDL VLDL secretion Endoplasmic Reticulum Early Golgi Kozlitina, Nat Genet 2014; Holmen, Nat Genet 2014; Mahdessian, PNAS 2014; Dongiovanni, Hepatology 2015

37 MBOAT7 rs C>T associates with hepatic fat content and NASH Hepatic TG content (%) CC P=.005 (IQR 2-8) (IQR 2-7) (IQR 2-6) N = Dallas Heart Study CT TT P=.008 NASH prevalence (%) N = Liver Biopsy Cohort

38 Common liver diseases share genetic risk factors of disease progression ALD NAFLD PNPLA3 TM6SF2 MBOAT7 Chronic Hepatitis C

39 PNPLA3 I148M and HCC risk in cirrhosis an individual patient data meta-analysis Allelic Odds Ratio 2,5 2 1,5 1 0, [ ] p= 2.8 x [ ] p= 3.5 x [ ] p=4.7 x n= 2, ,374 Trépo, Hepatology 2014

40 PNPLA3 I148M and progressive liver disease: a new paradigm in hepatology ALCOHOL Fructose Obesity and insulin resistance Hepatitis C virus PNPLA3 148I PNPLA3 148M Mild uncomplicated steatosis Direct carcinogenic activity Steatohepatitis & fibrogenesis PNPLA3 148M/M Cirrhosis Hepatocellular carcinoma Valenti, Hepatology 2012 Valenti, Dig Liver Dis 2013

41 PNPLA3 I148M is the major genetic determinant of alcoholic hepatitis PNPLA3 OR 1.87 p<10-14 Atkinson, EASL 2016

42 PNPLA3 I148M increases mortality in patients with severe alcoholic hepatitis HR 1.69 ( ) P rec =0.04 Atkinson, J Hepatol 2017

43 especially in those who quit drinking HR 2.77 ( ) P< P=NS HR 3.40 ( ) P rec = Atkinson, J Hepatol 2017

44 Impact on PNPLA3 I148M on liver damage resolution in heavy drinkers N= N= a=p<0.05; b=p<0.01 Rausch, W J Hepatol 2017

45 Key points : ALD is a leading cause of liver disease, and it is unlikely to decline The risk of ALD increases progressively over 30 g / day of alcohol intake, but only a minority of heavy drinkers gets alcoholic cirrhosis! Female sex, obesity-dysmetabolism and chronic viral infections are major cofactors in the pathogenesis progressive liver disease Abstinence is the key favorable prognostic factor Steatosis is the key pathophysiological mechanism The PNPLA3 I148M variant plays a major role in the susceptibility to ALD and acute hepatitis in heavy drinkers

46 PNPLA3 I148M as pharmacological target Lipid droplets PNPLA3 148I PNPLA3 148M STEATOHEPATITIS PHARMACOLOGICAL REDUCTION OF 148M PROTEIN EXPRESSION ( ) TAG remodeling Endoplasmic Reticulum Fatty acids Ub Ub Ub Obesity Insulin resistance CATABOLISM SECRETION RESTORATION OF TAG REMODELING AND DISMISSAL Proteasomal degradation Valenti, Hepatology 2017

47 Thank you for your attention!

48 Acknowledgements Metabolic Liver Diseases Lab, Milan Paola Dongiovanni Marica Meroni Raffaela Rametta Guido Baselli Alessandro Pietrelli Clinical center Silvia Fargion Anna Fracanzani Serena Pelusi Erika Fatta Cristina Bertelli Giuseppina Pisano Rosa Lombardi Monza Alberto Piperno INGM Raffaele Defrancesco Cristina Cheroni Torino Elisabetta Bugianesi Ester Vanni Udine Giorgio Soardo Verona Domenico Girelli Pathology Valentina Vaira Marco Maggioni Silvano Bosari Surgery Stefano Gatti Enrico Mozzi Roma Valerio Nobili Luca Miele, Anna Alisi Gothenburg Stefano Romeo Finland Jussi Pihlajamaki Hannele Yki-Jarvinen Humanitas University Massimo Colombo Alessio Aghemo Palermo Salvo Petta, Antonio Craxi Zurich/Dresden Felix Stickel Jochen Hampe Dallas Julia Kozlitina Stefan Stender New York Domenico Accili Utpal Pajvani Newcastle Quentin Anstee Helen Reeves Chris Day