natural history of alcoholic liver disease - aisf · [email protected]. acknowledgements...

Luca ValentiDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy

Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico

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, prof. Associato di Medicina InternaUniversità 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 discussionedi farmaci in studio o ad uso off-label

Outline

Overview and the role of steatosis

Traditional risk factors

Impact on chronic hepatitis C

A genetic point of view of the disease

Cause specific increase in mortality in alcoholic fatty liver disease - AFLD

0

10

20

30

40

50

60

Overall Liver disease CVD non-GI cancer Infection

2.6

19.7

2.1 2.3

6.7

General population

AFLD

NAFLD

9.4

59.9

2.7 2.2 4.1

Jepsen P, Hepato-Gastroenterology 2003

Temporal trends, USA

Goldberg, Gastroenterology 2017

HCVALDNAFLD

Ethanol AcetaldehydeNAD NADH

ADH

Ethanol + O2Acetaldehyde +H2O+ ROS

MEOS

NADPNADPH

1A- Alcohol dehydrogenase (ADH)

1B - MEOS (P450) - inducible

Acetaldehyde AcetateNAD NADH

2- Aldehyde dehydrogenase

Hepatic ethanol metabolism

CYP2E1

ALCOHOL

NADH

lipogenesis

beta-oxidation

FFAs flux AMPK

SREBP1c

Mitochondrialdamage

VLDL secretion

Pathogenesis of alcoholic steatosis

ROS

acetaldehyde

Acetate

Natural history of alcoholic fatty liver

Alcohol use with nutritionally complete diet

Normal Steatosis

AbstinenceResolves over 30 days RISK FACTORS:

Gender: femaleAlcohol use: daily or continued heavy

Histology: megamitochondria, severe or micro steatosis, inflammation

Comorbidities: obesity, hemochromatosis, chronic viral infections

HCC3-10%Fibrosis

Cirrhosis

2-3% / year90-95%

Steatohepatitis 10-35%

Natural history of alcoholic hepatitis

All were abstinent

Normal Alcoholic hepatitis87 pts, f-up to 9 yrs Cirrhosis

35-38%10-46%

19-52%

Galambos, Gastroenterology 1972Pares, J Hepatol 1986

Steatosis

SIBO

Alcohol

LPS

Increased intestinal permeability

TLR-4

TNFROS

TNF

Fatty acids

Adiponectin

IL-10

C3a/C5aMCP-1

Kupffercells

HSCs

TGF-

NK

TNF-R1

Resistin

IL-12

NKTIL-12

IFN-

MHC

T cells

Th1 cytokines

B cells

IL-6

IL-6IL-1

Valenti, Sem Immunopathol 2009

CYP2E1

Outline





Bellentani, Gut 1997; Corrao Prev Med 2004

Relationship between the amount of alcohol consumed and the probability to develop ALD

OR (95% ci)ALD

Cirrhosis

Ref NS 7.5 20.2 15.1 35.8(4-14) (9-43) (5-43) (16-82)

Ref NS 10.9 25.0 52.9 62.3(4-34) (8-79) (17-169) (20-193)

N=2,202

Lower threshold in females

Sorensen, Hepatology 1996

Aberg, Liv Int 2017

Association between Binge Drinking and risk of decompensated cirrhosis

(Per year)

Adjusted for sex and alcohol intake

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

Mortality for alcoholic liver disease in Europe in 2005 (WHO 2010)

Blachier, J Hepatol 2013

MEN

WOMEN

Excessive alcohol intake & obesity: synergistic effect on fatty liver

Bellentani, Ann Intern Med 2000

Relative risk of steatosis in the study groups

Study N ResultsNaveau 1604 Overweight >10y increases steatosis and cirrhosis

Raynard 268 BMI associated with fibrosis stage >F2

Protective effect of coffee intake on risk of cirrhosis (n=125,580)

Klatsky, Arch Intern Med 2006

Outline





Alcohol and HCV: effect of alcohol excessAuthor Study design N ResultsSerfaty, 1997 Case-control 168 30-80g/d increases risk of cirrhosis

Wiley, 1998 Case-control 176 Increases cirrhosis and decompensation

Pessione, 1998 Cross sectional 233 Increases replication and fibrosisprogression

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

Synergy between alcohol and HCV in determining liver disease

Punzalan, J Vir Hep 2016

Prevalence of alcohol use disorders in chronic hepatitis C in France, 2008–2013: A nationwide

retrospective cohort study (N=97,347)

Schwarzinger, J Hepatol 2017

29%

Risk of liver transplantation or premature death by alcohol use disorders and age in patients discharged with chronic HCV infection


Population attributable risk (PAR) of liver-related complications in patients discharged with chronic

HCV infection


Alcohol

Cirrhosis

Modified from Stickel, Gut 2011

Factors involved in the progression of ALD

Comorbidity

Metabolic syndrome

Chronic viral hepatitis

Nutrition

Iron storage

Gender

Ethnicity

Genetic variants

Host genetics

Outline





The genetic determinants of alcoholic cirrhosis

Buch, Stickel & Trepo, Nat Genet 2015

PNPLA3 I148M and progressive fibrosis

1 2 40.5

148M

AlcoholicLiver Disease

Odds RatioAdvanced fibrosis

Tian, Nat Genet 2009

Stickel, Hepatology 2010

Seth, Hepatology 2010

Trepo, Hepatology 2011

Burza, Liv Int 2013

Chronic HCVHepatitis

Valenti, Hepatology 2011

Muller, J Hepatol 2011

Trepo, Hepatology 2011

Valenti, AP&T 2012

Patin, Gastroenterology 2012

1 2 40.5

148M

Odds RatioAdvanced fibrosis

Allelic OR Allelic OR

see also meta-analysis: Salameh, Am J Gastroenterol 2015

ALD RISK

I/M vs. I/I

M/M vs. I/I

Modulation of the effect of the PNPLA3 I148M variant on steatosis and cirrhosis by alcohol

intake in CHC

Valenti, J Hepatol 2011

3

Tg

Endoplasmic Reticulum

Lipid droplets

Alcohol and obesity favor lipid droplets accumulation in hepatocytes

FFAs

Extracellularspace

VLDLsecretion

Early Golgi

TM6SF2167E Nascent

VLDL

ALCOHOLObesity

PNPLA3148I

HFC: 0-5%

Dongiovanni, BMC Research International, 2015


Lipid droplets

Romeo, Nat Genet 2008, He, J Biol Chem 2010; Ruhanen, J Lipid Res 2014; Dongiovanni, World J Gastroentorol2013; Dongiovanni, Hepatology 2014; Donati, Hepatology 2016; Basuray, Hepatology 2017

Impaired lipid droplets remodeling causes steatohepatitis in PNPLA3 I148M carriers

FFAs

Extracellularspace

VLDLsecretion

Early Golgi

TM6SF2167E Nascent

VLDL

PNPLA3148M

ALCOHOLObesity

Tg

HFC: 6%

ATGL(PNPLA2)

PNPLA3 has retynil-esterase activity in HSCs and the I148M variant is a loss of function

Retinyl-palmitate

PNPLA3InsulinTGF-

ETOH

Regeneration DifferentiationInihibition of lipogenesis

RetinolPalmitic acid

Retinal

Retinoic acid

ADH

ALDH

PNPLA3 148M

MMP2-TIMP1/2CCL5 – GMCSF

Tg


Lipid droplets

TM6SF2 is involved in lipidation of VLDL and secretion of lipids from hepatocytes

FFAs

Extracellularspace

VLDLsecretion

Early Golgi

TM6SF2167E Nascent

VLDL

ObesityInsulin resistance

PNPLA3148I

HFC: 0-5%

Dongiovanni, BMC Research International, 2015; Smagris, J Biol Chem 2016


Lipid droplets

Kozlitina, Nat Genet 2014; Holmen, Nat Genet 2014; Mahdessian, PNAS 2014; Dongiovanni, Hepatology 2015

Impaired VLDL secretion in E167K TM6SF2carriers causes fatty liver

FFAs

Extracellularspace

VLDLsecretion

Early Golgi

TM6SF2167K Nascent

VLDL


PNPLA3148I

HFC: 6%

MBOAT7 rs641738 C>T associates with hepatic fat content and NASH

CC TTCT

Hep

atic

TG

con

tent

(%)

2.0

2.5

3.0

3.5

4.0

(IQR 2-6) (IQR 2-7)

(IQR 2-8)P=.005

N = 1143 1219 374N

ASH

pre

vale

nce

(%)

16

18

20

22

24

N = 382 526 241

P=.008

Dallas Heart Study Liver Biopsy Cohort

Common liver diseases share genetic risk factors of disease progression

PNPLA3TM6SF2MBOAT7

ALD NAFLD

Chronic Hepatitis C

Alle

licO

dds

Rat

io

0

0,5

1

1,5

2

2,51.77

[1.42-2.19]p= 2.8 x 10-7

1.55[1.03-2.34]

p= 3.5 x 10-2

2.20[1.80-2.67]

p=4.7 x 10-15

945 1,374n= 2,503

Trépo, Hepatology 2014

PNPLA3 I148M and HCC risk in cirrhosisan individual patient data meta-analysis

Obesity andinsulin resistance

ALCOHOLFructose Hepatitis C virus

PNPLA3 148I

Mild uncomplicated steatosis

PNPLA3 148M

Steatohepatitis &

fibrogenesis

Cirrhosis

Valenti, Hepatology 2012Valenti, Dig Liver Dis 2013

PNPLA3 I148M and progressive liver disease:a new paradigm in hepatology

Hepatocellularcarcinoma

PNPLA3 148M/M

Directcarcinogenic

activity

PNPLA3 I148M is the major genetic determinant of alcoholic hepatitis

Atkinson, EASL 2016

PNPLA3OR 1.87p<10-14

PNPLA3 I148M increases mortality in patients with severe alcoholic hepatitis

Atkinson, J Hepatol 2017

HR 1.69(1.02-2.81)Prec=0.04

…especially in those who quit drinking

Atkinson, J Hepatol 2017

HR 2.77(1.79-4.29)P<0.0001

HR 3.40(1.54-7.49)Prec=0.0002P=NS

Impact on PNPLA3 I148M on liver damage resolution in heavy drinkers

Rausch, W J Hepatol 2017

N= 204 274 43 N= 204 274 43

a=p<0.05; b=p<0.01

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 ofalcohol intake, but only a minority of heavy drinkers getsalcoholic cirrhosis!

Female sex, obesity-dysmetabolism and chronic viralinfections are major cofactors in the pathogenesisprogressive liver disease

Abstinence is the key favorable prognostic factor

Steatosis is the key pathophysiological mechanism

The PNPLA3 I148M variant plays a major role in thesusceptibility to ALD and acute hepatitis in heavy drinkers

PNPLA3 I148M as pharmacological target

Valenti, Hepatology 2017


Lipid droplets

Fatty acids

PNPLA3 148I


TAG remodeling

PNPLA3 148M PHARMACOLOGICAL REDUCTION OF 148M

PROTEIN EXPRESSION( )

CATABOLISMSECRETIONUb

UbUb

STEATOHEPATITIS

Proteasomaldegradation

RESTORATION OF TAG REMODELING AND

DISMISSAL

Thank you for your attention!

[email protected]

AcknowledgementsMetabolic Liver Diseases Lab, Milan

Paola DongiovanniMarica MeroniRaffaela RamettaGuido BaselliAlessandro Pietrelli

Clinical centerSilvia FargionAnna FracanzaniSerena PelusiErika FattaCristina BertelliGiuseppina PisanoRosa Lombardi

UdineGiorgio Soardo

Humanitas UniversityMassimo ColomboAlessio Aghemo

INGMRaffaele Defrancesco

Cristina Cheroni

PathologyValentina VairaMarco MaggioniSilvano Bosari

NewcastleQuentin AnsteeHelen Reeves

Chris Day

GothenburgStefano Romeo

New YorkDomenico Accili

Utpal Pajvani

SurgeryStefano GattiEnrico Mozzi

TorinoElisabetta Bugianesi

Ester VanniRoma

Valerio NobiliLuca Miele, Anna Alisi

PalermoSalvo Petta, Antonio Craxi

Zurich/DresdenFelix Stickel

Jochen Hampe

DallasJulia KozlitinaStefan Stender

MonzaAlberto Piperno

VeronaDomenico Girelli

FinlandJussi Pihlajamaki

Hannele Yki-Jarvinen

natural history of alcoholic liver disease - aisf · [email protected]. acknowledgements...

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