Obesity and liver cancer

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ContentslistsavailableatScienceDirect

Annals

of

Hepatology

j o ur na l ho me p ag e:w w w . e l s e v i e r . e s / a n n a l s o f h e p a t o l o g y

Concise

reviews

Obesity

and

liver

cancer

Carlo

Saitta

a,∗

_,

_Teresa

_Pollicino

a,b

_,

_Giovanni

_Raimondo

a,c

a_Division_of_Clinical_and_Molecular_Hepatology,_Department_of_Internal_Medicine,_University_Hospital_of_Messina,_Italy b_Division_of_Clinical_and_Molecular_Hepatology,_Department_of_Human_Pathology,_University_of_Messina,_Italy

c_Division_of_Clinical_and_Molecular_Hepatology,_Department_of_Clinical_and_Experimental_Medicine,_University_of_Messina,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received12July2019 Accepted12July2019 Availableonline20August2019

Keywords:

Hepatocellularcarcinoma Intrahepaticcholangiocarcinoma Non-alcoholicfattyliverdisease Non-alcoholicsteatohepatitis Obesity

a

b

s

t

r

a

c

t

Obesityprevalenceisrapidlyincreasingworldwide.Itisassociatedwithhugeeconomicandhealthcosts duetoitsclinicalconsequences,whichincludesincreasedincidenceoftype2diabetes,cardiovascular diseases,anddevelopmentofdifferentmalignancies.Inparticular,obesityisanindependentriskfactor forthedevelopmentofhepatocellularcarcinoma(HCC).Indeed,obesityishighlyprevalentinpatients withnon-alcoholicfattyliverdisease(NAFLD)thatisbecomingoneofthemostfrequentcausesofliver diseaseworldwide.NAFLD-relatedHCCisthemostrapidlygrowingindicationforlivertransplantation inmanycountries.ThehighermortalityratesfoundinobeseHCCpatientsmightberelatednotonly toaworseoutcomeafterHCCtreatments,butalsotoadelayeddiagnosisrelatedtoalowfrequency andapoorerqualityofabdominalultrasonographysurveillancethatisthetestuniversallyusedforHCC screening.Givenitsdiffusion,obesityisfrequentlypresentinpatientswithchronicliverdiseasesrelated todifferentetiologies,andinthesecasesitmayincreasetheHCCrisk,actingasanadditionalco-factor. Indeed,growingevidencedemonstratesthatahealthydietandregularphysicalactivitymayhavean impactinreducingtheoverallHCCrisk.Finally,animpactofobesityinthedevelopmentofintrahepatic cholangiocarcinomahasbeenpostulated,butmoreextensivestudiesareneededtodeﬁnitivelyconﬁrm thisassociation.

1. Introduction

Obesityisrecognizedasaglobalpandemic,consideringthat

ﬁg-ureshavealmosttripledworldwidesince1975.TheWorldHealth

Organizationestimatedthatobesepeopleover18yearsofagewere morethan650millionin2016(about13%oftheworld’sadult pop-ulation[11%ofmenand15%ofwomen])[1].Furthermore,over340

millionchildrenandadolescentsaged5–19wereestimatedtobe

overweightorobesein2016,andthisimpliesthatthenumberof

obesesubjectswillincreaseinthenearfuture,giventhatchildhood obesityislinkedtoamuchhigherchanceofadultobesity[2],with allthenegativeeffectsintermsofhealthcareresourcesneededto dealwithitsconsequences.Indeed,thedevelopmentof cardiovas-culardiseasesandoftype2diabetesmellitus(T2DM)arethebest

knownobesity-relatedcomplications.However,obesityisalsoan

establishedriskfactorforthedevelopmentofseveralmalignancies,

suchasbreast,colorectal,endometrium,esophagus,gallbladder,

kidneyandpancreascancers,aswellasbone-marrow

malignan-cies(Fig.1)[3–6].Overall,obesityincreasesmortalityratesinall

∗ Correspondingauthor.

E-mailaddress:csaitta@unime.it(C.Saitta).

cancers,asshowedinastudyfromtheAmericanCancerSocietyin

whichsubjectswithabodymassindex(BMI)greaterthan40had

deathrateshigherthanthoseinnormalweightindividuals(52%

higherinmenand62%higherinwomen)[7].Onthebasisofthe

relativerisksandassociationsobservedinthisstudy,itwas

esti-matedthat14%ofalldeathsfromcancerinmenand20%inwomen

wereattributabletobeingoverweightorobeseinU.S.A.[7]. Alargebodyofevidenceshowsaparticularlystrongassociation betweenobesityandhepatocellularcarcinoma(HCC)[6,8–14],and thisconcisereviewwillfocusontheepidemiologicalandclinical aspectsofthelivercancersinobesepeople.

2. Theburdenofobesity-associatedHCC

HCCistheﬁfthmostfrequentcancerandthesecondleading

causeofcancer-relatedmortalityworldwideinmen[15].A

con-stantlyincreasingtrendofHCCincidenceandmortalityhasbeen

observedinU.S.A. andmany Europeancountries. In U.S.A.,HCC

showsanincidenceincreasingby4.5%annually,anditisreported tobethemostrapidlygrowingcauseofcancer-relateddeaths[16]. Mostcasesof HCCariseinthecontextoflivercirrhosis,mainly duetochronichepatitisBvirus(HBV)andchronichepatitisCvirus (HCV)infectionsand/orheavyalcoholdrinking[17].ChronicHBV

https://doi.org/10.1016/j.aohep.2019.07.004

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Breast cancer

Kidney cancer

Endometrial cancer

Hematological malignancies

Esophageal cancer Gallbladder cancer Colorectal cancer Pancreatic cancer LIVER HCC ICC? OBESITY

Fig.1. Malignanciesassociatedwithobesity.Abbreviations:HCC,hepatocellular car-cinoma.ICC,intrahepaticcholangiocarcinoma.

infectionis the leading causeof HCC worldwide and the main

riskfactorforHCCdevelopmentineasternAsiaandsub-Saharan

Africa,whilechronicHCVinfectionremainsanimportantrisk fac-torinU.S.A.andEurope.Indeed,thereisthehopethatthecure ofHCVbydirectantiviralagents(DAA)andtheefﬁcacious treat-mentsavailableagainstHBVwillreducetheratesofHCCincidence

andmortality.However,despitetheseveryimportantadvancesin

thetreatmentofviralhepatitis,livercancerisstillaglobally rec-ognizedhealthcareissue.Possibly,theimpactontheglobalHCC

incidenceratesoftheHCVcurebyDAAwillbecomemoreevident

overtime[18].Nevertheless,thereisclearevidenceofaconstant riseofHCCincidencethatiscommonlyattributedtotheparallel

increaseofnon-alcoholic fattyliverdisease(NAFLD),which has

becometheleadingcauseof liverdiseaseinmany areasofthe

world[19],withaprevalencereaching30%ofthegeneral

popu-lation[20,21].Inabout20%ofNAFLDsubjects,liverhistologymay showfeaturesofhepatitis–non-alcoholicsteatohepatitis(NASH)

–characterizedbythepresenceofnecro-inﬂammationandoften

ofﬁbrosis,potentiallyevolvingtowardcirrhosisandHCC[22,23]. NASH-relatedHCCisthemostrapidlygrowingindicationforliver transplantationinU.S.A.[24].

NAFLDis stronglyassociatedwithfeaturesof metabolic

syn-drome(MS),andtheprobabilityofdevelopingNASHincreaseswith

thenumberofriskfactorsinvolved(obesity,T2DM,hypertension

anddyslipidaemia)[25,26].Inameta-analysisstudyofglobal

epi-demiology,obesityprevalenceamongpatientswithNAFLDwas

estimatedat51.3%,whereasamongpatientswithNASHitwas

cal-culatedtobe81.8%[27].Notsurprisingly,givingthecontinuous

riseofobesityprevalence,NAFLDhasbecomethemostcommon

etiologicfactorofliverdiseaseworldwide[21].Thevery strong

associationbetweenHCCandMShasbecomemoreevidentinthe

lasttwodecades.Ofnote,obesityinitselfhasbeenshowntobean independentriskfactorofHCC[8].

Inacohortofabout18,000London-basedgovernment

employ-ees,followedupforamedianof28years,thehazardratio(HR)

ofHCCdevelopmentinobeseindividualswas3.76[9].A

meta-analysisofcohortstudiesassessingtheassociationbetweenobesity

andlivercancershowedthatoverweight orobesesubjectshad

a17%and 89%increasedrisk ofHCC,respectively,comparedto

normalweightindividuals[10].Anothermeta-analysis,evaluating prospectiveobservationalstudiesassessingthestrengthof associ-ationsbetweenBMIanddifferentsitesofcancer,showedthatthe riskoflivercancerincreasesbyabout25%foreach5kg/m2_increase ofBMI[11].Anadditionalmeta-analysisevaluated21prospective studies,showinga relativerisk ofHCCof1.39foreach5kg/m2

increaseinBMI,withthemostpronouncedriskincreaseamong

individualswithaBMI>32kg/m2_[12]_._A_systematic_review_of₁₀

cohortstudiesconductedin2010showedapositiveassociation

betweenobesityandrisk ofHCC inthemajority ofthestudies

OBESITY NAFLD NASH CIRRHOSIS HCC ?

Fig.2.SchematicrepresentationofthephasesconnectingobesitytoHCC.The questionmark(?)highlightsthehypothesisofahepatocarcinogenicroleof obe-sityindependentofthenon-alcoholicfattyliverdisease.Abbreviations:NAFLD, non-alcoholicfattyliverdisease.NASH,non-alcoholicsteatohepatitis.HCC, hepa-tocellularcarcinoma.

analyzed[13].Thenecessitytotakeactioninordertoreducethe spreadofchildhoodobesityisfurtherhighlightedbyaDanishstudy, revealingthathigherBMIinchildhoodincreasestheriskofprimary

livercancerinadults,withaHRofHCCdevelopmentof1.36per

unitincreaseinBMI[14].Despitethefactthatsomeofthesestudies havelimitations(particularlyrelatedtotheabsenceofdataonthe presenceofco-factorsofliverdamage[i.e.,hepatitisvirus infec-tionsand/oralcoholintake]),thelinkbetweenobesityandHCCis verystrongandunanimouslyconsideredunquestionable(Fig.2).

3. MortalityinobesepatientswithHCC

A milestoneepidemiology paperpublishedby Calleet al.in

2003,whichevaluatedmorethan900,000U.S.adults,showedthat

therelativeriskoflivercancer-relatedmortalityinsubjectswitha BMIbetween30and34.9kg/m2_and_in_those_with_a_BMI_>₃₅_kg/m2

was1.9 and4.5 timeshigher,respectively, thanthat ofnormal

weight individuals [7].Similarly, thepreviously reportedpaper

analyzingalargeEnglishpopulation,showedthatobese

individ-ualshadalivercancer-relatedmortality4timeshigherthanthat ofnormalweightsubjects[9].Recently,ameta-analysisincluding 9observationalstudiesforatotalnumberofmorethan1,500,000 individualsshowedthatobesesubjectshadatwo-foldincreaseof

HCC-relatedmortality.Suchassociationwasmoreevidentinmen

andWesternpopulations[28].AstudyconductedinUKshowed

that,between2000and2010,mortalityforlivercancerrose 1.8-fold,witha10-foldincreaseinHCCassociatedwithNAFLDandwith obesityandothermetabolicriskfactorsbeingpresentin66%ofthe cases,independentlyoftheunderlyingetiologyoftheliverdisease

[29].Obesitymayalsohaveanimpactontheoutcomeafterany

treatmentofthecancernodules.Inastudyanalyzingacohortof159 HCCpatientstreatedwithorthotopiclivertransplantation(OLT),an increasedincidenceoflife-threateningcomplicationswasfoundin

overweightandobesepatientscomparedtonormalweight

sub-jects,aswellasadoubledincidenceofHCCrecurrenceafterOLT (15%vs.7%)[30].InaU.S.retrospectivecohortof342HCCpatients

whounderwentOLTbetween1999and2010,aBMIhigherthan

30wasapredictorofHCCrecurrence,microvascularinvasionand

ofa pooroverallsurvival (OS),doublingthemortalityrisk after

transplantation [31].Anotherstudyperformedin Japanshowed

lowersurvivalratesinoverweightorobesepatientsundergoing

hepatectomyforrecurrentHCCcomparedtoindividualswith

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negativelyinﬂuencestheoutcomeafterHCCtreatments,andthis maybeduetoahigherriskofpostoperativecomplications[33]. However,inthiscontextitisworthytobementionedthatseveral

studiesshowedthatHCCpatientswithhigherBMIhaveabetter

outcomeafterhepatectomythanthosewithlowerBMI[34–36],

whereasotherstudiesdidnotﬁndanydifferenceinoutcomesafter surgeryinpatientswithdifferentBMI[37–39].

4. HCCsurveillanceinobesepatients

Bydeﬁnition,theaimofasurveillanceprogramistoachievea reductioninthemortalityratesofthetargetdiseasethroughan earlydiagnosis,anditshouldbecost-efﬁcient.Theusefulnessand theapplicabilityofthediagnostictestsusedforsurveillancedepend onmanyfactors,suchastheincidenceofthediseaseinthetarget populationandtheavailabilityofthetestitself.Patientsathighrisk

ofdevelopingHCCshouldbeincludedinasurveillanceprogram

thatessentiallyconsistsofanupperabdominalultrasonography

performedeverysix months[40,41].Patients withcirrhosis are

atthehighestriskofHCC(infact,morethan80%ofHCCarisein thecontestofadvancedliverdisease)[42].However,grayareas

exist,andthere isthepossibilityof thedevelopmentofHCC in

non-cirrhoticlivers,inparticularincaseswithHBVinfectionand

incaseswithNAFLD.However,therealriskofHCCdevelopment

innon-cirrhoticNAFLDpatientsisstillunknown.Itisestimated

thatabout50%ofNASH-associatedHCCariseinthecontextofa

non-cirrhoticliver[43,44],butsuchincidenceof livercanceris

considerednot sufﬁcienttopromoteanactiveultrasonographic

surveillance,consideringtheverylargeprevalenceof NAFLDin

thegeneralpopulation.Thus,timelydiagnosisofHCCarisingin

aNAFLDcontextisatruechallengeforthehepatologists,and

obe-sity–veryfrequentlypresentinNAFLDpatients–makesitmore

difﬁcult,becauseofahigherchanceofapoor-qualityultrasound examinationinobesesubjects.

InaU.S.studyexamining“Surveillance,EpidemiologyandEnd

Results”(SEER)registriesbetween2004and2009,andincluding

almost5000HCCpatients,thosewithNAFLD-associatedliver

can-cerwereolder,hadshorterOSandhighertumor-relatedmortality thanpatients withHCC related tootheretiologies [45].This is

mainlyduetoadelayinthediagnosisduetouncertaintyinthe

surveillancebeneﬁt.Theissuerelatedtothelackofsurveillance hasbeenassessedinastudyonU.S.veterans,showingthata

sig-niﬁcantlyhigherproportionofpatientswithNAFLD-relatedHCC

(56.7%)didnotundergosurveillanceinthe3yearsprecedingHCC

diagnosis,compared withHCCpatientswithalcohol-(40.2%) or

HCV-relateddisease(13.3%)[46].Consequently,alowernumberof

patientswithNAFLD-relatedHCChadthechancetoreceive

tumor-speciﬁctreatments[46].Aretrospectivecohortstudyconductedin theU.S.andincluding941patientsundergoingultrasound surveil-lanceforcirrhosisshowedthatobesepatientshad3–8-foldhigher

risk ofhaving aninadequate examination,with increasingBMI

leadingtoanincreasedriskoffailure.Infact,one-thirdofcirrhotics witha BMI>35 had a qualitativelyinadequate ultrasound [47]. Forthesereasons,thepossibilityofasurveillancewithcomputed

tomographyormagneticresonanceimaginghasbeenconsidered

forthesepatients,althoughitscost-effectivenesswouldbe imprac-tical.Indeed,thereisnoconsensusonwhatisthebestsurveillance

strategy– ifany– innon-cirrhoticobese patientswithNAFLD,

consideringthat theindividualriskof HCCdevelopmentis low,

particularlyifcomparedtotheriskincirrhoticsubjects[48,49].

Althoughgiventheactualincidenceratessurveillancecannotbe

recommendedinthissetting,itisundoubtedthatanefﬁcacious

HCCriskstratiﬁcationinnon-cirrhoticobesesubjectswithNAFLD isanunmetneedatpresent.

5. Obesityasariskco-factorofHCCdevelopmentin chronicliverdiseases

Becauseofitsdiffusion,obesityisfrequentlypresentinpatients withchronichepatitisBorCorwithalcoholicliverdisease,and itisconsideredanadditionalHCCriskfactorinthesesubjects.A

Taiwanesepopulation-basedstudy,conductedinabout24,000

sub-jects,revealedthatobesitywasassociatedwitha4-foldriskofHCC inanti-HCVpositivesubjects,a1.36-foldriskinHBV-infected,and a2-foldriskinsubjectswithoutviralinfections[50].Furthermore,

whenobesityanddiabeteswerepresenttogether,such

associa-tioncausedamorethan 100-foldincreasedriskofHCC inboth

HBVand HCVinfected subjects,suggesting apossible

synergis-ticeffectofmetabolicfactorsandviralhepatitis[50].AJapanese studywhichenrolledabout1500patientswithchronichepatitisC

showedthatoverweightandobesitywereindependentriskfactors

ofHCC,withaHRof1.86and3.1,respectively[51].A retrospec-tivestudyanalyzingliverbiopsiesfromHBVinfectedindividuals, showedthathistologicallydetectedliversteatosiswasan indepen-dentriskfactorforHCC(HR7.3)[52].Similarly,thepresenceof

radiologically-assessedNAFLDwasshown tobeariskfactorfor

HCCdevelopmentinchronichepatitis BpatientsinwhomHBV

wassuppressedbymeansofantiviraltherapy[53].Asynergistic effectofobesityandalcoholintakehasbeenidentiﬁedinastudy

prospectivelyevaluatingaTaiwanesepopulationwithchronic

hep-atitisB,wheretheriskofincidentHCCincreasedinbothoverweight (HR2.4)andobese(HR2.9)alcoholabusers[54].Alarge prospec-tivestudyfromUKhighlightedtheroleofobesityinpatientswith HCCarisinginthecontextofliverdiseasescausedbyother etiolo-gies,withmetabolicriskfactorsbeingpresentinuptotwo-thirds ofpatientswithHCC[29].Aretrospectiveanalysisconductedin

theU.S.onabout20,000explantedliversshowedthatobesitywas

anindependentpredictorof HCCinpatientswithalcoholic

cir-rhosis[55].Similarly,aFrenchretrospectivestudyanalyzing110

patientswithalcoholiccirrhosiswhounderwentOLTfoundthata

previoushistoryofbeingoverweightorobeseincreasedtherisk

ofHCC(oddsratio[OR]6.2),andthatthecontemporarypresence

ofT2DMincreasedtheriskwithanadditionaleffect(OR9.1)[56]. InacohortofFrenchpatientswithwellcompensatedalcoholicor

HCVrelatedcirrhosis,thecontemporarypresenceofobesityand

T2DMsigniﬁcantlyincreasedtheriskofHCCdevelopment(HR6)

[57].Altogether,thesedataconﬁrmthatobesityisanimportant additionalplayerinthedevelopmentofHCCinpatientswithliver diseaseduetodifferentcauses.

6. PossibleinterventionsforreducingHCCriskinobese patientswithNAFLD

GiventhestronglinkbetweenobesityandHCC,every

interven-tionaimedatreducingtheBMIatindividuallevelshouldreduce

theriskofHCCdevelopment.Theimpactofdietaryfactorsand

physicalactivityonHCChavebeenrecentlyreviewed[58].

Grow-ingevidencedemonstratesthatahealthydietmayhaveanimpact

inreducingtheriskofHCCdevelopment.Ithasbeenshownthat

a fruit-rich diet reduces HCC risk, while a low vegetable

con-sumptionincreasesthepossibilitiesof developingprimaryliver

cancer[59,60].Indeed,agoodadherencetoaMediterraneandiet appearstobeassociatedwitha50%reductionofHCCincidence[61].

Moreover,epidemiologic studieshave demonstratedthat

physi-calactivityisabletoreducetheriskofdifferentcancers[62–66]. Inalargeprospectively-followedTaiwanesecohort,acorrelation

betweenareducedriskofHCCandthedegreeofphysical

activ-itywasobserved[67].AnNIHstudyonabout500,000individuals

providedsimilarresults,showinga signiﬁcantdecreased riskof

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ofphysicalactivity[68].Concerningpharmacologicinterventions,

metforminaswellasstatinshavebeenassociatedwitha

signiﬁ-cantlyreducedriskofHCCindiabeticsanddysplipidaemicpatients

withNAFLD[69–74].However,studiesspeciﬁcallyfocusedonthe

useoftheabovedrugsinobeseindividualsarelacking.Bariatric

surgeryisawellrecognizedtreatmentofmorbidobesity,andit

hasbeenshowntoinducedisappearanceofNASHinabout85%

ofpatientsafteroneyearoffollowuppost-surgery[75].Thus,one mayspeculatethat–inthelong-term–thissurgicalapproachcould

bebeneﬁcialinreducingtheriskofHCCdevelopmentinmorbidly

obesepatients.However,thelackoflong-termfollowup

investi-gationsdonotallow–atpresent–toconﬁrmthishypothesis.

7. Istherealinkbetweenobesityandcholangiocarcinoma?

Cholangiocarcinoma(CC)is a malignanttumorof thebiliary

tract,thesecond mostcommonprimaryliver cancerafterHCC

[76].CCisclassiﬁedbasedonanatomiclocationsasintra-(ICC)or extrahepatic(ECC),whichareconsideredtwodistinctphenotypes, differingintheirpresentation,naturalhistory,management,and probablyalsointheirpathogenesis.ICCissimilartoHCCinits pre-sentation,andbothareoftenclassiﬁedasprimarylivercancersin

epidemiologicstudies.

Atpresent, contrasting data are availableon a possiblelink

betweenobesityandCC[77–80].However,whenthestudieswere

limitedtotheICC,theresultsshowinganassociationwithobesity

appeartobemoreuniform.Indeed,thestartoftheobesity

pan-demicintheU.S.A.precededbyabout10yearstherapidincrease

ofICC incidenceobservedin the1980s in thatcountry[81]. In

addition,datafromtheSEERprogramshowedthatMSwas

sig-niﬁcantlymorefrequentinpatientsdevelopingICC,andinthese

patientsobesitywasidentiﬁedasanindependentriskfactorofICC

[8].Alsoameta-analysisconﬁrmedthatobesityisanICCriskfactor

(OR1.6)[82].ArecentlypublishedpaperfromtheNational

Can-cerInstitutelinkedearlyadulthoodadipositytoICC.Inparticular,

itshowedthathigherBMIatage18 wasassociatedwitha34%

higherriskofsuccessiveICCdevelopment[83].Themostrecently publishedmeta-analysis,analyzingprospectivecohortsandnested case-controlstudies,revealedthatobesitywasassociatedwitha 49%increasedICCrisk[84].

8. Conclusions

Manyepidemiologicdatahaveidentiﬁedobesityasan

impor-tant risk factor for HCC development. Moreover, obesity is

associatedwithreducedsurvival inHCCpatients.Thismightbe

relatedtoalessefﬁcacioussurveillancestrategyandaconsequent

delay in diagnosiswith more limited possibility of therapeutic

interventions,althoughthepossibilityofaworseoutcomeafter

curativetreatmentsinthesepatientscannotberuledout.Withthe growingepidemicofobesity,aparallelincreaseoftheprevalence ofNAFLDisforeseen,makingitthecandidatetobetheworldwide mostimportantriskfactorforHCCdevelopmentinthenearfuture.

Abbreviations

BMI bodymassindex

CC cholangiocarcinoma

DAA directantiviralagents

ECC extrahepaticcholangiocarcinoma

HR hazardratio

HBV hepatitisBvirus

HCV hepatitisCvirus

HCC hepatocellularcarcinoma

ICC intrahepaticcholangiocarcinoma

MS metabolicsyndrome

NAFLD non-alcoholicfattyliverdisease

NASH non-alcoholicsteatohepatitis

OR oddsratio

OLT orthotopiclivertransplantation

OS overallsurvival

SEER surveillanceepidemiologyandendresults

T2DM type2diabetesmellitus

Financialsupport

Thisresearchdidnotreceiveanyspeciﬁcgrantfromfunding

agenciesinthepublic,commercial,ornot-for-proﬁtsectors.

Conﬂictsofinterest

Theauthorshavenoconﬂictsofinteresttodeclare.

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