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

Thankyou!

Danielle.Brandman@ucsf.edu