Fatty liver: The Silent Epidemic What is it and what can we do to fight it? Danielle Brandman, MD, MAS Associate Professor of Medicine Program Director, Transplant Hepatology Fellowship Director, UCSF Fatty Liver Clinic
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