Fattyliver:TheSilentEpidemic
Whatisitandwhatcanwedo
tofightit?
DanielleBrandman,MD,MASAssociateProfessorofMedicine
ProgramDirector,TransplantHepatologyFellowshipDirector,UCSFFattyLiverClinic
Outline
▪ NAFLDbasics
▪ NAFLD:diagnosisandstaging
▪ ComplicationsofNAFLD
▪ ManagementofNAFLD
Whatisnonalcoholicfattyliverdisease(NAFLD)?
▪ Nonalcoholicfattyliverdisease(NAFLD)occurswhenfatisdepositedintheliver,withoutothercausesoffattyliveridentified
NAFLD
NAFLFatwithoutinflammation
NASHFat+
inflammation
NASH
+
fibrosis
Cirrhosis20-30%ofNASH
HCC
NAFLD:Non-AlcoholicFattyLiverDiseaseSpectrumofdisease
NAFLD
NAFLFatwithoutinflammation
NASHFat+
inflammation
NASH
+
fibrosis
Cirrhosis20-30%ofNASH
HCC
NAFLD:Non-AlcoholicFattyLiverDiseaseSpectrumofdisease
?
NAFLD
NAFLFatwithoutinflammation
NASHFat+
inflammation
NASH
+
fibrosis
Cirrhosis20-30%ofNASH
HCC
NAFLD:Non-AlcoholicFattyLiverDiseaseSpectrumofdisease
??
WhoisatriskforNAFLD?
▪ Metabolicsyndrome:– Obesity(“apples”>“pears”)– Highbloodsugar– Highbloodpressure– Highcholesterol(and/orlow“good”cholesterol)
WhoisatriskforNAFLD?
▪ Otherriskfactors– Hispanicethnicity– Hereditary/genetic– Polycysticovariansyndrome(PCOS)– HIV– Sleepapnea– Hypothyroidism
PrevalenceofSelf-ReportedObesityAmongAdults,2016
Epidemiology
▪ PrevalenceofNAFLD:___USpopulation
▪ PrevalenceofNASH:___%population
Epidemiology
▪ PrevalenceofNAFLD:16-29%USpopulation
▪ PrevalenceofNASH:2-7%population
Farrell,Hepatology,2006.
Younoussi,Hepatology,2015.
Epidemiology
▪ PrevalenceofNAFLD:16-29%USpopulation– 2/3ofobeseadults– 84-96%bariatricsurgerypopulation– Upto76%ofdiabetics
▪ PrevalenceofNASH:2-7%population– 10-30%ofNAFLD– 20%ofobeseadults
Farrell,Hepatology,2006.
Younoussi,Hepatology,2015.
HowwouldIknowifIhaveNAFLD?
▪ Symptoms– Many(upto77%)ofpatientsmayhavenone– Fatigue(50-75%;mayinpartberelatedtosleepapnea)– Right-sidedabdominalpain
HowwouldIknowifIhaveNAFLD?
▪ Symptoms– Many(upto77%)ofpatientsmayhavenone– Fatigue(50-75%;mayinpartberelatedtosleepapnea)– Right-sidedabdominalpain
▪ Presenceofriskfactors(e.g.,obesity,diabetes)
HowwouldIknowifIhaveNAFLD?
▪ Symptoms– Many(upto77%)ofpatientsmayhavenone– Fatigue(50-75%;mayinpartberelatedtosleepapnea)– Right-sidedabdominalpain
▪ Presenceofriskfactors(e.g.,obesity,diabetes)
▪ Labtests:elevationofALT>AST(usualpattern)
▪ Radiology:fatcanbeseenonultrasound,MRI,orCTscan
HowwouldIknowifIhaveNAFLD?
▪ Screeningofthegeneralpopulationisnotcurrentlyrecommended– USguidelines(AASLD)suggesthighlevelofsuspicioninhighriskpatients
– Europeanguidelines(EASL)recommendscreeningallpatientswithobesityormetabolicsyndromewithliverenzymesandultrasound
ShouldIseealiverspecialistifIhaveNAFLD?
ShouldIseealiverspecialistifIhaveNAFLD?
▪ Accuratediagnosis– Makesurenootherformsofliverdisease– Determinewhichsub-typeofNAFLDyoumayhave(NAFL
vsNASH)– Evaluateforliverscar(fibrosis)– Liverbiopsymaybeneeded
▪ Monitoring– Lookforsignsofworseningofliverscar– Specialmonitoringifcirrhosispresent
HowisNAFLDdiagnosed?
HowisNAFLDdiagnosed?
▪ Establishpresenceoffatintheliver:ultrasound,MRI,orbiopsy
▪ Eliminateothercausesofliverdisease(bloodtests)
▪ Alcoholintake<2drinksperday
▪ Nomedicationsknowntocausefattyliver(e.g.,prednisone,tamoxifen)
HowisNAFLDdiagnosed?
▪ Establishpresenceoffatintheliver:ultrasound,MRI,orbiopsy
▪ Eliminateothercausesofliverdisease(bloodtests)
▪ Alcoholintake<2drinksperday
▪ Nomedicationsknowntocausefattyliver(e.g.,prednisone,tamoxifen)
NAFLDisadiagnosisofexclusion
RoleofliverbiopsyinNAFLD
▪ ClassifyNAFLDaccurately:NASHvsNAFL
▪ Determinefibrosisstage
▪ Eliminateothercausesofliverdisease
RoleofliverbiopsyinNAFLD
▪ ClassifyNAFLDaccurately:NASHvsNAFL
▪ Determinefibrosisstage
▪ Eliminateothercausesofliverdisease NASH
Advancedfibrosis
Pros
• Mostreliablemeansforexcludingalternativeetiology/co-existingliverdisease
• “Goldstandard”fordiagnosisandstaging
Pros
• Mostreliablemeansforexcludingalternativeetiology/co-existingliverdisease
• “Goldstandard”fordiagnosisandstaging
Pros
• Mostreliablemeansforexcludingalternativeetiology/co-existingliverdisease
• “Goldstandard”fordiagnosisandstaging
Cons
• Samplingerror• Riskofcomplications• Expense• ImpossibletoapplytolargeNAFLDpopulation
TransientElastography:Fibroscan
Fibroscan
▪ Factorsthatmayproduceinaccurateresults:– Obesity– NASH– Alcoholuse– Nonfastingstate– Abnormallivertests(ALT>100,elevatedalkalinephosphatase)– Hispanicethnicity
▪ Requiresadequateexperiencetoproducereliableresults
Vuppalanchi, Hepatology, 2017.
Whyisaccuratediagnosisandstagingimportant?
NAFLD:Non-AlcoholicFattyLiverDisease
Spectrumofdisease
NASH 7 years per 1 stage
~28 years 0à cirrhosis
NAFL 14 years per 1 stage
~56 years 0à cirrhosis
PrognosisofNAFLDbyfibrosisstage
Steatosis
NASH ± F1-F2 fibrosis
HCC
Death/ LTx Cirrhosis
Advanced F3 fibrosis
12-40%
5-10%
0-50%
8%
13%
25-50%
14%
25%
7%
Day, J Hep, 2008.
WhataretheconsequencesofNAFLD?
WhataretheconsequencesofNAFLD?
▪ Leadingcausesofdeath1. Heartdisease2. Cancer3. Endstageliverdisease
NAFLDandLiver-relatedevents
▪ Severityofliverfibrosisisthemostimportantpredictorofdeath
▪ PatientswithNAFLDareatriskforlivercancer(HCC)– 7-8-foldgreaterthanthegeneralpopulation
– RiskinNASHcirrhosis:6.7-15%at5-10years
– Unlikeotherdiseases,cirrhosismaynotneedtobepresent
NASHisincreasingasanindicationforlivertransplantation
Wong, Gastroenterology, 2015.
2
NASHistheleadingindicationforLTinwomen
Noureddin,AJG,2018.
WhattreatmentsareavailablethatimproveNASH?
WhattreatmentsareavailablethatimproveNASH?
WhattreatmentsareavailablethatimproveNASH?
WeightLoss
• Goal: loss of 7-10% baseline weight to improve NASH and fibrosis
• Diet ¡ Portion control and simple carbohydrate avoidance
¡ Avoid fructose-sweetened beverages
Harrison. Hepatology, 2009. Promrat, Hepatology , 2010 Vilar-Gomez, Gastro, 2015 Chalasani , Hepatology 2012 .
WeightLoss
• Exercise ¡ Exercise alone reduces liver fat
o Aerobic >150-250 minutes per week o Resistance training 45 minutes/day x 3 days/week
Harrison. Hepatology, 2009. Promrat, Hepatology , 2010 Vilar-Gomez, Gastro, 2015 Chalasani , Hepatology 2012 .
Exercise
Examples Light Walking slowly, computing, cooking,
washing dishes Moderate Walking briskly, light biking,
vacuuming, mowing lawn Vigorous Jogging, fast biking, Zumba,
shoveling, carrying heavy loads
BarrierstoexerciseAssociatedcomorbidities
▪ Obstructivesleepapnea:fatigue,headache
▪ Osteoarthritis:pain,decreasedmobility
▪ Depression:decreasedactivityandmotivation
▪ Balanceproblems
▪ Generalizedweakness
▪ Cognitivedeficits
Gerber, Clin Liver Dis, 2014.
Prescriptionforexercise:behavioralstrategies
▪ Motivation
▪ Attainable
▪ Measurable
▪ Memory
▪ Positivethoughts
▪ Reinforcement
▪ Environmentalsupport
▪ Stressmanagement
▪ Socialsupport
▪ ProblemsolveGerber, Clin Liver Dis, 2014.
WeightLoss
• Bariatric Surgery ¡ Foregut procedures (Sleeve gastrectomy,
Roux-en-Y gastric bypass, Lap band) ¡ Improvement in NAFL/NASH +/- fibrosis ¡ Relatively contraindicated in patients with
cirrhosis o If needed, laparoscopic sleeve
gastrectomy by an experienced surgeon is the operation of choice
Harrison. Hepatology, 2009. Promrat, Hepatology , 2010 Chalasani , Hepatology 2012 .
TreatmentofMetabolicSyndromeinNAFLD
▪ Statins– SafeforuseinNAFLD
– PotentialbenefitsofNAFLD/liverenzymeimprovementandreducedriskofliverdeathorHCC
▪ Notproveninrandomizedcontrolledtrials
▪ Metformin– SafeforuseinNAFLD
– Somestudiesshowimprovementinliverbiopsyandliverenzymes
▪ Notproveninrandomizedcontrolledtrials
– Possibleanti-neoplasticeffects
MedicationstotreatNAFLD
▪ Onlypatientswithbiopsy-provenNASHneedliver-specifictreatment
▪ MedicationscurrentlyavailablerecommendedfortreatmentofNASH– VitaminE– Pioglitazone(Actos)
05
101520253035404550
Vit E Placebo Pioglitazone
% ImprovedP = 0.001 P = 0.04
43% 34%
19%
ImprovementinNASHonLiverBiopsy
Study included only non-diabetics
NAFLDpathways/targetsfortreatment
Rotman, Gut, 2017.
▪ Phase3clinicaltrials:– Cenicriviroc– Elafibranor– Obeticholicacid
▪ Atleast40othermedicationsinphase1andphase2trials
FuturepotentialNASHtreatment
NAFLD:sharedmanagementbetweenprimarycareandhepatology
Brandman, CLD, 2019.
IsitsafetodrinkalcoholifIhaveNAFLD?Ifso,howmuch?
▪ NASHprevention?– PossiblebenefitsofmodestalcoholintakeonpresenceofNASH▪ AnyalcoholusemaypreventimprovementinNAFLDovertimeandmayincreasefibrosisprogression
Dunn,JHepatol,2012.Ajmera,ClinGastroHep,2018.Ekstedt,WorldJGastro,2009.
AlcoholandNAFLD
▪ OnceNASH/NAFLdiagnosed:– ModestormoderatealcoholintakemaypreventimprovementinNAFL/NASH
– Bingedrinkingisassociatedwithfibrosisprogressioninpatientswithpre-existingNAFLD
Dunn,JHepatol,2012.Ajmera,ClinGastroHep,2018.Ekstedt,WorldJGastro,2009.
AlcoholandNAFLD
AlcoholandNAFLD
Norecommendations/dataregarding“safe”alcoholintakeinpatientswith
establishedNASH
Summary
▪ NAFLDiscommon,andmostpatientswithmetabolicsyndromecomorbiditieswillhaveNAFLD,withatleast16millionintheUShavingNASH
▪ NAFLDisanumbrellatermthatincludesNAFLandNASH– NASH>>>NAFLhasriskofprogressiontocirrhosis– BiopsyisneededtocharacterizeNAFLD
▪ LeadingcauseofdeathinNAFLD:Heartdisease
▪ NAFLDisanimportantcontributortolivercancerandneedforlivertransplant
Summary
▪ Managementhingesonweightloss,exercise,avoidingcarbohydrates,metabolicsyndromecontrol– VitaminE(?pioglitazone)onlyforbiopsy-provenNASH– ManydrugsinthepipelineforNASHandfibrosis
Future/ongoingareasforresearch
▪ Bestmethodforscreeninganddiagnosis
▪ Whichpatientsareatgreatestriskfordiseaseprogression– NAFLàNASH– NASHorNAFLàcirrhosis
▪ Impactoffuturetreatmentsonoutcomes– Needforlivertransplant– DevelopmentofHCC– Liver-relateddeath– Cardiovasculardisease