2012BTS+英国移植学会：非酒精性脂肪性肝炎患者的肝移植

BritishTransplantationSocietyGuidelinesfor

LiverTransplantationfor

PatientswithNon-AlcoholicSteato-Hepatitis

FirstEdition

April2011

Contents

1 Guidelinedevelopment 3

2 Gradingofrecommendations 5

3 Summaryofrecommendations 6

4 Abbreviations 11

5 PrevalenceofNASHcirrhosisintheUK 12

6 IndicationsforlivertransplantationinNASH-relatedcirrhosis 14

7 AssessmentofoperativeriskinNAFLDpatientsundergoinglivertransplantation 16

8 Assessmentandmanagementofnutritionalstatusduringtransplantwork-up 23

9 SurgicalaspectsoflivertransplantationforpatientswithNAFLD 27

10 Peri-operativemonitoring 30

11 Immunosuppression 33

12 Post-transplantmonitoringofNASHpatientsanddiseaserecurrence 36

13 Post-transplantmanagementofNAFLD 39

14 Non-alcoholicfattyliverdiseaseinchildren 43

15 TransplantationforNASH–thepatients’perspective 45

16 Statementsofpotentialconflictsofinterest 47

17 References 50

1Guidelinedevelopment

NASHisanincreasingcauseofliverdiseasenecessitatinglivertransplantation.InpatientswithadvancedNASH,thereareoftenco-existentclinicalissuesthatimpactontheoutcomeoflivertransplantation.

TherearenoguidelinesfortheassessmentandmanagementofpatientswithNASHundergoinglivertransplantation.AgroupwasthereforeinvitedbytheCounciloftheBritishTransplantationSociety(BTS)toprepareguidelinesforthemanagementofNASHbeforeandafterlivertransplantation.ThefirstdraftwaswrittenbyDr

PN

Newsome(SeniorLecturerandConsultantHepatologist,LiverUnit,UniversityHospitalBirminghamNHSFoundationTrust)inAutumn2010withcontributionsfromthefollowingguidelinegroup:DrPHenriksen(ConsultantCardiologistandHonorarySeniorLecturer,EdinburghHeartCentre,NHSLothian,UniversityHospitalsDivision),ProfCPDay(ProfessorofLiverMedicine,InstituteofCellularMedicine,NewcastleUniversity),DrDThorburn(ConsultantHepatologist,LiverUnit,RoyalFreeHospital,London),Mr

DFMirza(ConsultantHepatobiliaryandTransplantSurgeon,LiverUnit,UniversityHospitalBirminghamNHSFoundationTrust),DrJWFerguson(ConsultantHepatologistandHonorarySeniorLecturer,LiverUnit,UniversityHospitalBirminghamNHSFoundationTrust),DrGAuzinger(ConsultantIntensiveCareMedicine,LiverIntensiveTherapyUnit,King’sCollegeHospitalLondonNHSFoundationTrust),DrMAllison(ConsultantHepatologist,LiverUnit,DepartmentofMedicine,CambridgeUniversityHospitalNHSFoundationTrust),DrJWTomlinson(ReaderinEndocrinology,CentreforEndocrinology,Diabetes&Metabolism,UniversityofBirmingham),Ms

H

Manley(BritishLiverTrust),DrKJSimpson(SeniorLecturerinHepatology,UniversityofEdinburgh&HonConsultantPhysicianScottishLiverTransplantationUnit,RoyalInfirmaryEdinburgh),ProfSGHubscher(LeithProfessorandProfessorofHepaticPathology,UniversityofBirminghamandConsultantHistopathologist,UniversityHospitalBirminghamNHSFoundationTrust),DrCMillson(ConsultantHepatologist,StJames'sUniversityHospital,Leeds),DrJOben(WellcomeTrustSeniorLecturerandConsultantHepatologist,UniversityCollegeLondon,CentreforHepatology,RoyalFreeHospital,RowlandHill,LondonNW32PF),ProfJMNeuberger(AssociateMedicalDirectorforOrganDonationandTransplantation,NHSBloodandTransplantandHonoraryConsultantPhysicianQueenElizabethHospitalBirmingham),DrPJMcKiernan(ConsultantPaediatrician,LiverUnit,BirminghamChildren'sHospital)andDrJIWyatt(ConsultantHistopathologist,StJames'sUniversityHospital,Leeds).

Thisfollowedasystematicreviewoftheliteratureusingretrievalfromelectronicdatabasesandreadingsuggestionsfromcolleagues.

Thedocumentwasrevisedintheautumnandwinterof2010,principallybyDrPNNewsomeandDrPAAndrews(Chair,BTSStandardsCommittee).ThelastdateofliteraturereviewwasNovember2010.AdraftversionwascirculatedtomembersoftheBTSCouncilandplacedontheBTSwebsiteforcommentinMarch2011.ThefinalversionwasrevisedinthelightofcommentsreceivedandpublishedinApril2011.

TheseguidelinesrepresentconsensusopinionfromexpertsintheUnitedKingdominthefieldsofhepatology,transplantationandrelateddisciplines.Theyrepresentasnapshotoftheevidenceavailableatthetimeofwriting.Itisrecognisedthatrecommendationsaremadeevenwhentheevidenceisweak.ItisfeltthatthisishelpfultocliniciansindailypracticeandissimilartotheapproachadoptedinotherBTSguidelines.Althoughitisbelievedthattheinformationpresentedisafairsummaryofcurrentevidenceandbestpractice,neithertheauthorsnortheBritishTransplantationSocietycanbeheldresponsibleforanyerrorsoromissions.Theguidelinesarenotdesignedtobeproscriptive,nortodefineastandardofcare.Dosesofprescribeddrugsshouldalwaysbecheckedbytheresponsibleclinicianaccordingtotherelevantinformationprovidedbythemanufacturersofthedrugs.

Itisanticipatedthattheseguidelineswillberevisedin2015.

2Gradingofrecommendations

Foreachrecommendation,assessmentshavebeenmadeofthequalityofsupportingevidenceandthestrengthoftherecommendation.Thisisinkeepingwithothernationalguidelinegroups

ADDINREFMGR.CITE<Refman><Cite><Author>O'Shea</Author><Year>2010</Year><RecNum>25414</RecNum><IDText>Alcoholicliverdisease</IDText><MDLRef_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>25414</Ref_ID><Title_Primary>Alcoholicliverdisease</Title_Primary><Authors_Primary>O'Shea,R.S.</Authors_Primary><Authors_Primary>Dasarathy,S.</Authors_Primary><Authors_Primary>McCullough,A.J.</Authors_Primary><Date_Primary>2010/1</Date_Primary><Keywords>Alcoholic</Keywords><Keywords>Algorithms</Keywords><Keywords>DA</Keywords><Keywords>diagnosis</Keywords><Keywords>DISEASE</Keywords><Keywords>Gastroenterology</Keywords><Keywords>Hepatitis,Alcoholic</Keywords><Keywords>Humans</Keywords><Keywords>La</Keywords><Keywords>Liver</Keywords><Keywords>liverdisease</Keywords><Keywords>LiverDiseases,Alcoholic</Keywords><Keywords>LiverTransplantation</Keywords><Keywords>REVIEW</Keywords><Keywords>RiskFactors</Keywords><Keywords>therapy</Keywords><Reprint>NotinFile</Reprint><Start_Page>307</Start_Page><End_Page>328</End_Page><Periodical>Hepatology</Periodical><Volume>51</Volume><Issue>1</Issue><Misc_3>10.1002/hep.23258[doi]</Misc_3><Address>DepartmentofGastroenterologyandHepatology,ClevelandClinicFoundation,Cleveland,OH44195,USA</Address><Web_URL>PM:20034030</Web_URL><ZZ_JournalStdAbbrev><fname="System">Hepatology</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>

(1,2)

.

Foreachrecommendation,thequalityofevidencehasbeengradedasoneof:

LevelA Dataderivedfrommultiplerandomisedclinicaltrialsormeta-analyses.

LevelB Dataderivedfromasinglerandomisedtrial,ornon-randomisedstudies.

LevelC Consensusopinionofexperts,casestudies,orstandard-of-care.

Foreachrecommendation,thestrengthofrecommendationhasbeenindicatedasoneof:

ClassI Conditionsforwhichthereisevidenceand/orgeneralagreementthatagivenevaluation,procedureortreatmentisbeneficialandeffective.

ClassII Conditionsforwhichthereisconflictingevidenceand/oradivergenceofopinionabouttheusefulness/efficacyofanevaluation,procedureortreatment.

ClassIIa Weightofevidence/opinionisinfavourofusefulness/efficacy.

ClassIIb Usefulness/efficacyislesswellestablishedbyevidence/opinion.

ClassIII Conditionsforwhichthereisevidenceand/orgeneralagreementthatanevaluation/procedure/treatmentisnotuseful/effectiveandinsomecasesmaybeharmful.

3Summaryofrecommendations

CriteriafordiagnosisofNASHgroupshouldincludeanestablishedclinicalandhistologicaldiagnosisofNASHonliverbiopsy,orahistologicaldiagnosisofcryptogeniccirrhosiswithaclinicalphenotypecompatiblewithunderlyingNASH,asdefinedbythepresenceof3ormorecomponentsofthemetabolicsyndromepriortoLT.(LevelC,ClassI)

CriteriaforconsiderationoflistingforlivertransplantationinpatientswithNASHcirrhosiseitherduetoESLDorpresenceofhepatocellularcarcinomashouldbeinlinewithstandardnationalcriteria.(LevelC,ClassI)

AlthoughthediagnosisofNASHcirrhosisshouldnotberegarded,initself,tobeariskfactorforpooroutcomeintheperi-operativeperiodoflivertransplantation,

cardiovascularriskshouldbecloselyconsideredinpatientswithNASHastheyhavemoreriskfactorsforcardiovasculardiseaseandarelikelytorequirefurthernon-invasivetesting.(LevelC,ClassI)

AllNAFLDpatientsshouldundergopre-operativeriskstratificationtoexcludesymptomaticcoronaryarterydiseaseandassessmentforthepresenceofstructuralheartdisease,leftventriculardysfunctionandpulmonaryhypertension.(LevelC,ClassI)

CardiovascularriskshouldbecloselyconsideredinpatientswithNAFLDasmanywillrequirefurthernon-invasivetesting.(LevelC,ClassI)

Patientsunabletoachieve4METs,orthosewithatleasttwointermediateriskfactors,shouldbeconsideredforfurthercardiactesting.(LevelC,ClassI)

Withinatransplantcentre,cardiologyinputshouldbeprovidedbycardiologistswithaninterest/experienceintheassessmentofpatientswithliverdisease.(LevelC,ClassI)

Thefollowingmoderateriskgroupsshouldbediscussedearlywithacardiologist:(i)patientswithchestpainofpossiblecardiacorigin;and(ii)patientsreceivingtreatmentforestablishedcoronarydiseaseorpreviouscoronaryrevascularisation.(LevelC,ClassI)

ThereisinsufficientevidencetorecommendasinglestresstestforNAFLDpatientsundergoingOLTassessment.Thechoiceoftestwillbeinpartdeterminedbylocalexpertise.(LevelC,ClassI)

Patientsshouldreceivea-blockerpriortolivertransplantation.Thisshouldbetitratedgraduallyandnotstartedintheimmediateperi-operativeperiod.(LevelB,ClassIIa)

Statinsshouldbestartedbetween30daysandatleast1weekbeforesurgery,orcontinuedinthosepatientsalreadyreceivingthem.(LevelB,ClassI)

Therearenodatatosupportanabsolutecut-offforbodymassindex(BMI)andlivertransplantation,althoughpatientswithaBMI>40kg/m2arelikelytohaveanincreasedpost-operativeandlong-termmortality.BMIshouldbecorrectedforthepresenceofascitesandperipheraloedema.(LevelC,ClassIIa)

Weightlossshouldnotberecommendedinallpatientswithend-stageliverdiseaseduetotheriskofprotein-caloriemalnutrition.(LevelC,ClassIII)

Forpatientswithstablecirrhosisandhepatocellularcarcinoma,itmaybeappropriatetotryandachieveweightlossbeforeproceeding/whilstwaitingforatransplant.(LevelC,ClassII)

AllpotentialNAFLDtransplantrecipients,includingthosewithapparentobesity,shouldbeassessedbyadieticianandsupplementalfeedingconsideredifrequired.(LevelC,ClassI)

Dietaryassessmentofpatientsbeingassessedforlivertransplantationshouldincludeuseofhand-gripstrength,anthropometryand/orsubjectiveglobalassessmenttoobjectivelydefinethepatient’snutritionalstatusandallowsupplementationifrequired.(LevelB,ClassI)

Dietaryassessmentofpatientsshouldberepeatedonanannualbasiswhilsttheyremainonthewaitinglistforlivertransplantation.(LevelB,ClassI)

Considerbariatricsurgeryatthetimeoflivertransplantationinrecipientswithseveremorbidobesity,thosewithfailedtreatmentofobesityorinpatientswithrecurrentdiseaseundergoingretransplantation.(LevelC,ClassIIa)

Considerbariatricsurgeryinrecipientswithseveremorbidobesity,thosewithfailedtreatmentofobesity,orinpatientsdevelopingprogressiveNASHwithfibrosisintheallograft.(LevelC,ClassIIa)

Whilstthereislikelytobeanincreasedoperativerisk,thelackofevidencefromcontrolledclinicaltrialsindicatesthatnorecommendationcanbemadeabouttheuseofintra-operativecardiacoutputmonitoring.(LevelB,ClassII)

Moderatelytightglucosecontrol(6-10mmol/l)shouldbetargetedduringtheearlyposttransplantcourseinpatientsofallaetiologies.(LevelA,ClassII)

Ifstartedpre-operatively,statintherapyshouldbecontinuedduringthepost-operativephase.(LevelB,ClassI)

AlongsideimmunosuppressionwithCNIandanti-metabolite,considerationshouldbegiventoeitherasteroid-freeregimeorearlysteroidwithdrawal(withinthreemonths)inpatientswithNASH.Wheresteroid-freeregimesareused,inductiontherapy(suchasATGorIL2-Rantagonism)shouldbeconsidered.(LevelB,ClassIIa)

Tacrolimuslevelsshouldbe<10ng/mlwithinthefirstthreemonthsafterlivertransplantationand5-8ng/mlafterthattoreducetheimpactonrenalfunctionanddyslipidaemia.Mycophenolateshouldbeusedasthepreferredanti-metabolite,topermitlowerlevelsoftacrolimus.(LevelB,ClassIIa)

Closefollow-upandearlyrecognitionandtreatmentoftherecognisedconsequencesoftransplantationandimmunosuppression(suchasweightgain,hypertension,hyperlipidaemia,diabetesandrenalimpairment)remainthekeytopreventingexcessriskfromrecurrentNAFLD.(LevelC,ClassI)

Histologicalexaminationoftheexplantedlivershouldbecarriedouttoconfirmthepresenceoffeaturescompatiblewithend-stageNASHandtoexcludefeaturessuggestinganalternativediagnosis.(ClassI,LevelC)

Themainroleofbiopsyistotheallowdiagnosisandstagingofliverhistopathology.WhereNAFLDistheonlyordominantpathology,liverallograftbiopsiescanbescoredusingtheKleinerclassification.Biopsiesperformedelsewhereshouldbereviewedatthetransplantcentretoensurereproducibility.(ClassI,LevelC)

Post-transplantmonitoringofpatientsshouldincludeaninitialUSSatoneyear,followedbyeverytwoyears,lookingforthepresenceofanechobrightliver.(ClassIIa,LevelC)

Post-transplantmonitoringofpatientswithechobrightliveronUSSshouldincludeprotocolliverbiopsiestodetectdiseaserecurrence,asliverfunctiontestsmaybenormal.Repeatbiopsyshouldbeconsideredeverythreeyears,unlessthereisaclinicalindicationformorefrequentbiopsies.(ClassIIa,LevelC)

Post-transplantpatientsshouldreceivesupport,adviceandtreatmentinorderachieveatargetbodymassindexof<25kg/m2.Thisshouldbeinthecontextofamultidisciplinaryteam,incorporatingdietarymodification,exerciseinterventionandthepotentialuseofpharmacotherapyandsurgicalinterventionwhereappropriate.(LevelC,ClassI)

Post-transplantpatientsshouldbescreenedforthepresenceofdiabetesand,ifpresent,reviewedregularlyforthedevelopmentofcomplications.GlycaemiccontrolshouldbeoptimisedinaccordancewithNICEguidance.(LevelA,ClassI)

PatientstransplantedforNAFLDshouldbemonitoredona6-monthlybasisforriskfactorsforcardiovasculardisease(BP,lipids,HbA1c),whichshouldbeaddressedwiththeintentionofreducingcardiovascularevents.(LevelII-3,LevelC)

Abloodpressuretargetof140/90mmHg(130/80mmHginpatientswithdiabetesand/orrenaldysfunction)shouldbeaimedfor(LevelA,ClassI).

Anti-hypertensiveagentssuchascalciumchannelblockersorACEinhibitorsshouldbeconsideredinviewoftheirpossibleadditionaleffectsofabrogatingliverfibrosis.(LevelC,ClassII)

AtargetLDLcholesterolof<2.6mmol/lisadvisedasthe10-yearcardiovasculareventrateexceeds20%forthelivertransplantpopulation.PravastatinandezetimibearepreferredagentsinviewoftheirdemonstratedefficacyandabsenceofinteractionswithCNIs.(LevelC,ClassIIa)

Thereisaneedtoincreaseunderstandingofliverdiseaseanditsmanycauses,toimprovepatientoutcomesandtoreducethestigmamanypatientsexperience.(NotGraded)

ThepotentialcardiovascularmorbidityassociatedwithNASHshouldbediscussedwithpatientsandguidancegivenondietandexercise,andsourcesofsupport(includingpsychologicalsupport)aspartofongoingmanagement.(NotGraded)

Provisionofindependentpre-andposttransplantemotionalandpsychologicalcounsellingandsupportisveryimportant,alongwithanopportunitytoprovideconfidentialfeedbacktothetransplantteampost-operatively.(NotGraded)

39.PatientswithNASHshouldbereferredtospecialistcentresforoptimalmanagementandconsiderationforclinicaltrials.(NotGraded)

4Abbreviations

ATG Anti-thymocyteglobulin

CKD Chronickidneydisease

CNI Calcineurininhibitor

CPX Cardiopulmonaryexercise

DSE Dobutaminestressechocardiography

ESLD End-stageliverdisease

HCC Hepatocellularcarcinoma

HCV HepatitisCvirus

IGB Intra-gastricballoon

IMS Immunosuppression

LV Leftventricular

LT Livertransplant

MELD Modelforend-stageliverdisease

MET Metabolicequivalentoftask

MI Myocardialinfarction

mPAP Meanpulmonaryarterypressure

mTORi Mammaliantargetofrapamycininhibitor

NAFLD Non-alcoholicfattyliverdisease

NASH Non-alcoholicsteato-hepatitis

NHSBT NationalHealthServiceBloodandTransplant

NODAT Newonsetdiabetesaftertransplantation

OLT Orthotopiclivertransplant

PASP Pulmonaryarterysystolicpressure

PAC Pulmonaryarterycatheter

PCWP Pulmonarycapillarywedgepressure

PCM Protein-caloriemalnutrition

RWMA Regionalwallmotionabnormalities

RV Rightventricular

SGA Subjectiveglobalassessment

TOE Trans-oesophagealechocardiography

TR Tricuspidregurgitation

5PrevalenceofNASHcirrhosisintheUK

Non-alcoholicfattyliverdisease(NAFLD)encompassesaspectrumofdiseaserangingfromsimplesteatosis,tosteatohepatitis(NASH)andcirrhosis.NAFLDiscloselyassociatedwithobesityandrepresentsthehepaticmanifestationofthemetabolicsyndrome.TheprevalenceofNAFLDhasrisenrapidlyinparallelwiththedramaticriseinlevelsofobesityanddiabetesmellitus

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(3)

,resultinginitnowbeingthecommonestcauseofliverdiseaseintheWest

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(4)

.

NAFLDprevalence

TheprevalenceofNAFLDisbetween20-30%inWesternadults

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(5,6)

,risingto90%inextremeobesity

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(7)

.NAFLDaffects3%ofthegeneralpaediatricpopulation,risingto53%inobesechildren

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(8,9)

,withimplicationsforfuturediseaseburden.NASH,themoreadvancedandclinicallyimportantformofNAFLD,hasanestimatedprevalenceof2-3%inthegeneralpopulation

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(10)

and37%inthemorbidlyobese

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(7)

.Steatosiswaspresentin70%ofalargecohortofpatientswithtype2diabetes

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(11)

.TheForesightreportpredictedthatwiththealarminggrowthofobesity,theburdenofNAFLDonprimarycareandliverserviceswilldoublefromacurrentannualcostof£4.2billionby2050

ADDINREFMGR.CITE<Refman><Cite><Author>Aylott</Author><Year>2007</Year><RecNum>25343</RecNum><IDText>TacklingObesities:theForesightReport</IDText><MDLRef_Type="Report"><Ref_Type>Report</Ref_Type><Ref_ID>25343</Ref_ID><Title_Primary><fname="TimesNewRoman">TacklingObesities:theForesightReport</f></Title_Primary><Authors_Primary>Aylott,J,</Authors_Primary><Authors_Primary>Brown,I.</Authors_Primary><Authors_Primary>Copeland,R.</Authors_Primary><Authors_Primary>Johnson,D.</Authors_Primary><Date_Primary>2007</Date_Primary><Keywords>Obesity</Keywords><Reprint>NotinFile</Reprint><Web_URL><u>.uk/idk/core/page.do?pageId=8267926</u></Web_URL><ZZ_WorkformID>24</ZZ_WorkformID></MDL></Cite></Refman>

(12)

.

Associationwithincreasedmortalityandprogressiontolivercirrhosis

PatientswithadiagnosisofNAFLDhavebeenshowntohaveasignificantlyhigheroverall

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(13-17)

andliver-related

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(14,15)

mortalitywhencomparedwithanage/sex-matchedgeneralpopulation.InpatientswithNASH,thelimiteddataavailablepointtoapproximatelyonethirdofpatientsdevelopingprogressivefibrosisovera5period,withupto9%developingcirrhosis

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(18,19)

.TheriskfactorsforprogressiveNASH-relatedliverdiseaseareobesity,type2diabetesmellitus,insulinresistanceandolderage.CurrentevidencesuggeststhatthenaturalhistoryofNASHcirrhosisissimilartothatofhepatitisCcirrhosiswithrespecttodecompensation

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(20,21)

.Hepatocellularcarcinoma(HCC),arecognisedcomplicationofcirrhosisofanumberofaetiologies,isalsoknowntooccurinNASH-relatedcirrhosis,andalsorarelyinpre-cirrhoticNASH

ADDINREFMGR.CITE<Refman><Cite><Author>Starley</Author><Year>2010</Year><RecNum>820</RecNum><IDText>Nonalcoholicfattyliverdiseaseandhepatocellularcarcinoma:aweightyconnection</IDText><MDLRef_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>820</Ref_ID><Title_Primary>Nonalcoholicfattyliverdiseaseandhepatocellularcarcinoma:aweightyconnection</Title_Primary><Authors_Primary>Starley,B.Q.</Authors_Primary><Authors_Primary>Calcagno,C.J.</Authors_Primary><Authors_Primary>Harrison,S.A.</Authors_Primary><Date_Primary>2010/5</Date_Primary><Keywords>AgeFactors</Keywords><Keywords>Carcinoma</Keywords><Keywords>Carcinoma,Hepatocellular</Keywords><Keywords>complications</Keywords><Keywords>DevelopedCountries</Keywords><Keywords>DiabetesComplications</Keywords><Keywords>etiology</Keywords><Keywords>FattyLiver</Keywords><Keywords>Fibrosis</Keywords><Keywords>Gastroenterology</Keywords><Keywords>Hepatitis</Keywords><Keywords>HepatitisC</Keywords><Keywords>HepatitisC,Chronic</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Insulin</Keywords><Keywords>InsulinResistance</Keywords><Keywords>Iron</Keywords><Keywords>Liver</Keywords><Keywords>LiverCirrhosis</Keywords><Keywords>LiverNeoplasms</Keywords><Keywords>metabolism</Keywords><Keywords>Obesity</Keywords><Keywords>Prevalence</Keywords><Keywords>Risk</Keywords><Keywords>RiskFactors</Keywords><Reprint>NotinFile</Reprint><Start_Page>1820</Start_Page><End_Page>1832</End_Page><Periodical>Hepatology</Periodical><Volume>51</Volume><Issue>5</Issue><Misc_3>10.1002/hep.23594[doi]</Misc_3><Address>DepartmentofMedicine,DivisionofGastroenterologyandHepatology,BrookeArmyMedicalCenter,FortSamHouston,TX78234,USA</Address><Web_URL>PM:20432259</Web_URL><ZZ_JournalStdAbbrev><fname="System">Hepatology</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>

(22)

.AprospectivestudyonNASHcirrhoticshasfoundacumulativeincidenceof2.6%forthedevelopmentofHCCinthispatientgroupcomparedto4.0%forpatientswithHepatitisCvirus(HCV)cirrhosis

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(23)

.ObesityanddiabeteshavebeenfoundtoberiskfactorsforthedevelopmentofHCCincirrhosisofavarietyofaetiologies

ADDINREFMGR.CITE

ADDINEN.CITE.DATA

(24,25)

.ThemortalityofpatientswithNAFLDrangesfrom12.6%over7.6yearsfollow-upinmixedcohortstobetween20.2-59.5%insecondarycarecohorts(13.7-21yearsfollow-up).Inthemostrecentstudywith21yearsoffollow-up,thiscorrespondedtoanexcessmortalityof70%(standardisedmortalityratio1.7;95%CI1.24-2.25)

ADDINREFMGR.CITE<Refman><Cite><Author>Soderberg</Author><Year>2010</Year><RecNum>783</RecNum><IDText>Decreasedsurvivalofsubjectswithelevatedliverfunctiontestsduringa28-yearfollow-up</IDText><MDLRef_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>783</Ref_ID><Title_Primary>Decreasedsurvivalofsubjectswithelevatedliverfunctiontestsduringa28-yearfollow-up</Title_Primary><Authors_Primary>Soderberg,C.</Authors_Primary><Authors_Primary>Stal,P.</Authors_Primary><Authors_Primary>Askling,J.</Authors_Primary><Authors_Primary>Glaumann,H.</Authors_Primary><Authors_Primary>Lindberg,G.</Authors_Primary><Authors_Primary>Marmur,J.</Authors_Primary><Authors_Primary>Hultcrantz,R.</Authors_Primary><Date_Primary>2010/2</Date_Primary><Keywords>AlanineTransaminase</Keywords><Keywords>Biopsy</Keywords><Keywords>blood</Keywords><Keywords>CauseofDeath</Keywords><Keywords>Enzymes</Keywords><Keywords>FattyLiver</Keywords><Keywords>Female</Keywords><Keywords>Follow-UpStudies</Keywords><Keywords>Humans</Keywords><Keywords>Liver</Keywords><Keywords>LiverDiseases</Keywords><Keywords>LiverFunctionTests</Keywords><Keywords>Male</Keywords><Keywords>MiddleAged</Keywords><Keywords>mortality</Keywords><Keywords>ProspectiveStudies</Keywords><Keywords>Registries</Keywords><Keywords>Research</Keywords><Keywords>RetrospectiveStudies</Keywords><Keywords>Risk</Keywords><Keywords>SurvivalRate</Keywords><Keywords>TimeFactors</Keywords><Keywords>Transaminases</Keywords><Reprint>NotinFile</Reprint><Start_Page>595</Start_Page><End_Page>602</End_Page><Periodical>Hepatology</Periodical><Volume>51</Volume><Issue>2</Issue><Address>DepartmentofMedicine,KarolinskaInstitute,Solna,Stockholm,Sweden.cecilia.soderberg@ki.se</Address><Web_URL>PM:20014114</Web_URL><ZZ_JournalStdAbbrev><fname="System">Hepatology</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>

(16)

.

Needforlivertransplantation

TheincreaseinthenumberofpatientswithadvancedliverdiseasesecondarytoNASH,aswellasassociatedHCC,willimpactonthepotentialfuturedemandforlivertransplantation(LT).AnalysisofNationalHealthServiceBloodandTransplant(NHSBT)datashowsthatinboth2008and2009,12%ofpatientsplacedontheelectiveLTwaitinglistwerecategorisedashavingNASHcirrhosis,with14.8%oftheseindividualslistedwithHCC.Consistentwiththeknownassociationwithinsulinresistance,49.1%ofpatientswithNASHcirrhosislistedforLTwerediabeticcomparedto22.1%ofallotherregisteredpatients(althoughthecriteriaforthedefinitionofdiabeteswerenotwelldefined).

6IndicationsforlivertransplantationinNASH-relatedcirrhosis

GiventhatlivertransplantationisarelativelyrecentlyidentifiedindicationforpatientswithNASH,dataforlongtermfollow-uparemorelimitedwhencomparedwithLTfortheothercausesofchronicliverdisease.Nevertheless,datafromseveralAmericancentressuggestthatpatientswithNASHd