RIUNIONEMONOTEMATICAAISF2017
Correlation ofALDandchronic HCVinfection inliver disease
Alcoholic Liver Disease:
TheNewChallenge
CosimoColletta,MD
Chief ofHepatologyDepartmentofMedicine
COQOmegna
Friday 6thOctober 2017
Disclosure Slide
CosimoColletta,MD- ChiefofHepatologyDepartmentofMedicine,COQOmegna
§ I DO NOT have any significant or other financial interests inthe subject matter of this presentation
and
§ I DO NOT intend to discuss an unlabeled, unapproved orinvestigative use of a commercial product or device.
§ Please feel free to use, update, and share some or all of theseslides in your noncommercial presentations to colleagues.
Correlation ofALDandchronic HCVinfection inliver disease
§ Alcohol andFibrosis Progression inHepatitis CVirusInfection
Alcohol andFibrosis Progression inHepatitis CVirusInfection
§ Inpatients infected withthehepatitis Cvirus,20%to30%willprogresstocirrhosis inovertwo tothree decades
§ Viral andhost factors that areimportant intheclinical andhistologicprogression ofHCVinfection
§ Alcohol consumption canworsen thecourse ofchronic hepatitis C
§ Most studies oftheeffect ofalcohol onhepatitis Chave focused onpersons who use50g/day ormoreofalcohol
§ Theadverse effects oflightandmoderateamounts ofalcohol intakeonhepatitis Cinfection have not been clearly shown
Poynard T,etal.Lancet1997;349:825-832
Mean serum HCVRNAlevels (branched DNA)according toSRACexpressed as grams perweek
Pessione F,etal.HEPATOLOGYVol.27,No.6,1998
Factors Correlated WithSerum HCVRNA:Uni- andMultivariateAnalyses
Pessione F,etal.HEPATOLOGYVol.27,No.6,1998
Alcohol andHCVRNA
§ The available literature on the effects of alcohol on viralreplication and serum HCV RNA levels is conflicting
§ An increase in HCV quasispecies has been reportedassociated with heavy drinkers (70 g/day) comparedwith nondrinkers
§ Other studies have not found a difference in HCV RNAlevels related to alcohol intake
BellentaniS,etal.Gut 1999;44:874-880KhanKN,etal.AlcoholAlcohol2000;35:286-295
Association between stageoffibrosis andage orduration ofinfection byalcohol consumption
Poynard T,etal.Lancet1997;349:825-832
Association between stageoffibrosis andage orduration ofinfection bycauseofinfection
Poynard T,etal.Lancet1997;349:825-832
Summary ofBreakdownofVariables AccordingtoFibrosis ScoreonLiver Biopsy
Ostapowicz G,etal.Hepatology Vol.27,No.6,1998
Scoresforsteatosis,necroinflammatory grading,andfibrosisstagingaccordingtoIshak’s criteria
C.Rigamonti etal.Hepatology,Vol.38,No.1,2003
Biopsy for 125 patients with chronic hepatitis C and no alcohol intake (groupA), ethanol intake < 50 g/d (group B), and ethanol intake > 50 g/d (group C)
Poynard T,etal.Lancet1997;349:825-832
Rateoffibrosis progression inpatients byrisk factors
Alcohol,HCVandsexdifferences
§ Chronic hepatitis Cis often histologically milder inwomenthan men.Fibrosisprogressionperyearwas0.154formenand0.111forwomen
§ However,women may bemoresensitivetotheadverseeffects ofalcohol andtherisk ofcirrhosis was twice as highinwomen as inmenwiththesame amount ofalcohol intake
§ Loweramounts ofalcohol were required fortheincreasedrisk offibrosis progression inwomen withchronic hepatitis C
Poynard T,etal.Lancet1997;349:825-832BellentaniS,etal.Gut 1997;41:845-850
Lightormoderatealcohol usewas not associatedwithfaster rates offibrosis progression
KellyE.M.etal.Clinical Infectious Disease 2017
HistologicResultsintheHCVandHCV/AlcoholGroup
Cirrhosiswas21⁄2timesasfrequentintheHCV/alcoholgroup.BoththemeanfibrosisgradeaswellasthemeanHAIscoresweresignificantlygreaterintheHCV/alcoholgroup
Therelationshipbetweenfibrosisgradeandyearsofexposure
T.E.WILEYetal.HepatologyVol.28,No.3,1998
The linear relation in patientswho did not drink
The linear relation in the combinedHCV/alcohol group
Histologic Activity,Fibrosis Score,andClinical Findings OverFour Decades ofHCVExposure WithorWithout Alcohol
T.E.WILEYetal.HepatologyVol.28,No.3,1998
Fibrosis scoreandtheyears ofexposure
§ Inthenonalcohol group,thefibrosis scoreincreased 1gradeevery 14years.IntheHCV/alcohol group fibrosisscoreincreasing 1gradeevery 7years
§ Inthefirstdecade,theHAIwas twofold greater inthealcohol group (P .05).
§ However,there was nostatistical increase inthefibrosisgradeorincidence ofcirrhosis inthefirstdecade
§ However,bythesecond decade58%ofpatients intheHCV/alcohol group had cirrhosis whereas only 12%oftheHCV-only group had cirrhosis (P .001).
T.E.WILEYetal.HepatologyVol.28,No.3,1998
Independent andCombined ActionofHepatitis CVirusInfection andAlcohol Consumption
Alcohol consumption has astrongeffect ontherisk ofLCthat is independent ofanti-HCVstatus
§ Adose-effect relationship between LDAIandtherisk ofLCwas also observed inanti-HCV-negativesubjects;theORwas not significantly foralcohol intake 50g/day,whereas itsteadily increased above this dosage
§ This finding allows us tofirmly reject thehypothesis ofapermissiverole ofHCVinthedevelopment ofliver damageinalcoholics
§ Thus,alcohol andHCVinteract synergically ontherisk ofliver cirrhosis
Anti-HCVpositivity does not modify theeffect oflow alcohol consumption
§ Thepractical consequence is that anti-HCVpositivesubjectswithout evidence ofliver disease should not beadvised tostopalcohol but should moderateits intake tonomorethan 30g/day
§ However,other factors could modify theeffect ofa‘‘low’’doseofalcohol inanti-HCVpositivesubjects
§ Alcohol intake andHCVinfection areindependent risk factorsforsymptomatic liver cirrhosis,but insubjects withhighlevels ofalcohol intake thecoexistence ofHCVinfection multiplies thealcohol-associated risk ofonset ofliver cirrhosis
Dionysos study
§ An alcohol intake less than 30 g/day did not increase therisk of clinically apparent cirrhosis
§ Among HCV-positive individuals who drank more than 30g/day of alcohol, 32% had cirrhosis compared with 10%of those who drank less
§ The combination of hepatitis C and alcohol abuse wasassociated with younger age at hospitalization andhigher rate of death compared with hepatitis C oralcoholic liver disease alone
Correlation ofALDandchronic HCVinfection inliver disease
§ Alcohol andHCC
Relationbetween alcohol drinking andHCCalso considering hepatitis Cvirus
§ Alcohol intake has been recognized as acauseofchronic liverdiseases,including hepatocellular carcinoma(HCC)
§ Theeffect ofalcohol drinking is evident even intheabsenceofhepatitis Cvirusinfection
§ Alcohol could beinvolved inthedevelopment ofHCCthrough both direct (genotoxic)andindirect mechanisms
§ Noagreement exists onthedose-effect relationbetweenalcohol intake andrisk ofHCC
Alcohol andHCC
§ Excess alcohol intake was shown topredisposetothedevelopment ofliver cancer intheDionysos study
§ Studies fromJapanreported anincreased risk ofHCCinpatients withhepatitis Cwho were drinking morethan 65gdaily formorethan 5years
§ Thetumors fromheavy drinkers were moreanaplastic withincreased capsular,extracapsular,andportal vein invasion andintrahepatic metastases.
§ Theheavy drinkers withHCCalso had ashortened survival
KuboS,etal.Surgery1997;121:425-429.
Alcohol andHCC
Heavy alcohol intake increases therisk ofHCCthrough thedevelopment ofcirrhosis,there is nodefiniteevidence toshowcarcinogenic potential ofalcohol
Inchronic HCVpatients,odds ofdeveloping cirrhosis were 2.3higher inheavy alcohol drinkers
Therisk ofHCCincreased inalinearfashionwithheavy alcoholintake,andthis risk doubled inthose infected withHCV.
Theeffect oflow ormoderateamount ofalcohol intake onriskofHCCis unclear.
MittalS,etal.JClin Gastroenterol.2013July;47(0):S2–S6
Liver carcinogenesis:theeffects ofearly andlatealcohol intake andinteraction withHCV
DonatoF,etal.Am J Epidemio 2002;155(4)323-331
Alcohol andHCC
Odds ratios for hepatocellular carcinoma, according to alcohol intakeand the presence of hepatitis CvirusRNA
Distributionofcases andodds ratios according toalcohol intake andthepresence ofHCVinfection
Alcohol intake (g/day)
The odds ratio for drinking >60 g/day of ethanol was 7.0 for subjects negativefor both infections, whereas the odds ratios for drinking 0–60 and >60 g/daywere, respectively, 55 and 109 for subjects positive for hepatitis C virus RNA
Donato F, et al. Am J Epidemiol Vol. 155, No. 4, 2002
Theinteraction betweenalcohol consumption andviral hepatitis
§ Alcohol drinking has a“pure”effect inincreasing therisk ofHCCandthat its effect canbemodified byHCVinfection
§ Asynergism between alcohol drinking andinfection wasfound,withapproximately atwofold increase intheodds ratioforhepatitis virusinfection fordrinkers of>60gperday
§ Thus,heavy alcohol intake increases therisk ofcirrhosis andliver cancer inhepatitis C,but therole oflightormoderateintake has not been adequately assessed
Donato F, et al. Am J Epidemiol Vol. 155, No. 4, 2002
Correlation ofALDandchronic HCVinfection inliver disease
§ Alcohol andSurvival
Risk ofdeath inpatients withhepatitis Candalcohol intake
§ Multiple studies have shown increased rates of cirrhosis,and risk of death in patients with hepatitis C who haveheavy alcohol intake
§ Unfortunately, most studies have evaluated theextremes of alcohol intake
§ The lower amounts of alcohol intake (cutoff of 30 g/day)found that at these levels worsened the rate ofdevelopment of fibrosis in hepatitis C, but the degree ofworsening was not statistically significant
Mortality related tochronic hepatitis C
§ Excessive alcohol consumption was animportantcofactor associated withmortality
§ Excessive alcohol consumption was strongly associatedwithayounger age at death suggesting amajorcontributing role ofalcohol inprematuredeath forthose chronically infected withHCV
P.Marcellin etal./JournalofHepatology48(2008)200–207
Meanageatdeathaccordingtoexcessivealcoholconsumption
Deaths related toHCVinfection occurred atanearlierageinpatientswithahistoryofexcessive alcohol consumption
P.Marcellin etal./JournalofHepatology48(2008)200–207
Excessive alcohol consumption was found for 35 percent, and the meanage at death was significantly lower when excessive alcoholconsumption was present (p = 0.004)
Theimpactofexcessive alcohol consumptionandchronic hepatitis Conmortality
Inpatients,withexcessive alcohol use,having CH-Cdramaticallyincreased therisk ofall-causemortality andliver-related mortality
Younossi Z.M.etal.AlimentPharmacol Ther 2013;37:703-709
Correlation ofALDandchronic HCVinfection inliver disease
§ Alcohol andTreatmentofHepatitis C
5-yearcumulativeincidence rateofHCC
A. 5 year incidence rate of HCC according to alcohol intakeB. 5-yearincidence rateofHCCaccording toviral eradicationC. 5-yearincidence rateofHCCaccording toalcohol intake andviral eradication
Hernaez R,etal.Annals ofHepatology 2017;16(1):16-20Vandenbulcke H.etal.JournalofHepatology 2016vol.65j543–551
5-yearcumulativeincidence rateofHCC
§ The5-yearcumulativeincidencerateofHCCwas10.6%inabstainersand23.8%inalcoholconsumers(p=0.087)
§ AverageannualHCCrateswere2.3%and5.9%inabstainersandconsumers,respectively
§ The5-yearcumulativeincidencerateofHCCwas2.0%inpatientswithviraleradicationand21.7%inpatientswithoutviraleradication(p=0.002).
§ AverageannualHCCrateswere0.4%and5.4%inpatientswithandwithoutviraleradication.
Vandenbulcke H.etal.JournalofHepatology 2016vol.65j543–551
5-yearcumulativeincidence rateofdecompensation andrateofmortality
AssociationbetweenHCVtreatmentstatusandalcoholuse:multivariableanalysis
R.KNIGHTetal.Addiction 27MAY2017
A significant decrease (over 60% reduction) in both hazardous alcohol use and bingedrinking and a reduction of 10 alcohol units/month were observed after HCV treatment
Perceived health andalcohol useinpatients withhepatitis C
§ Individuals who feel poorly may not see value inavoiding risk behaviors,perhaps duetohopelessnessorperceived futility
§ Among HCVinfected,drug-using individuals,thosewho perceived their health morenegatively generallyhad greater alcohol use,when all demographiccharacteristics were held constant
Drinkingstatusbyperceivedhealthstatusfordrug-usingindividualswithHCVinfection
0
20
40
60
80
100
Excellent Good Fair Poor
39,58 43,22 42,37 50,786,25 7,84 10,71 6,25
54,17 48,94 46,92 42,97Abstainer
Drinker
RiskyDrinker
J.C.Elliottetal./Addictive Behaviors 72(2017)21–26
Poorperceivedhealthmayresultinperceivedfutilityinhealthbehaviors
Drinkingstatusbyperceivedhealthstatusfordrug-usingindividualswithHIV/HCVco-infection
0
20
40
60
80
100
Excellent Good Fair Poor
46,67 46,38 46,4860,87
0 8,7 11,2713,0453,33 44,93 42,2526,09
Abstainer
Drinker
RiskyDrinker
J.C.Elliottetal./Addictive Behaviors 72(2017)21–26
Poorperceivedhealthmayresultinperceivedfutilityinhealthbehaviors
Animportant opportunity
§ ThetreatmentofHCVrepresents animportant opportunity toenhance apatient’s awareness andknowledge about liverhealth andtoprovide them withtheresources they need toreduceharmful alcohol useeffectively.
§ Enhancing anintegrated setofservices that targetother keyrisk behaviours,including theuseoftobacco andexcessiverates ofcannabis,represent important avenues forimprovingthefuturehealth outcomes ofpatients treated forHCV
Tsui J.I,etal.DrugandAlcoholDependence169(2016)101–109
SVRrates byAUDIT-CcategoryandHCVgenotype
Tsui J.I,etal.DrugandAlcoholDependence169(2016)101–109
SVRrates byAUDITCcategory accordingtocirrhosis andHIVstatus
Alcohol useandHCVtreatmentoutcomes amongpatients who areusing newer DAAtherapies
§ Findings support clinicians in following the currentclinical guidelines, which do not recommend excludingpersons who consume alcohol (HCV Guidance, 2017)
§ Findings of sensitivity analyses, however, also supportclinicians in continuing to recommend alcohol abstinencefor HCV-infected patients
Conclusion
§ Present datasuggest that ingestion ofmorethan 30g/day ofalcohol is harmful inpersons withchronic hepatitis C
§ Heavy alcohol use(morethan 50gdaily)worsens fibrosis,increases risk ofcirrhosis andincreases risk ofHCC
§ Thedeleterious effects ofheavy daily alcohol intake onthecourse ofchronic hepatitis Cis incontrovertible,but theeffectsoflesser amounts ofalcohol areunclear
§ Patients withahistory ofalcohol abuse ordependence shouldbeasked tobeabstinent andneed tobesupported byprofessional counseling
§ Moderatealcohol intake should not beanexclusion criteria fortreatmentofhepatitis C
