BOLDMRI与脂肪肝.docx

BOLDMRI与脂肪肝.docx

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BOLDMRI与脂肪肝

CarbogenGas–ChallengeBOLDMRImaginginaRatModelofDiethylnitrosamine-inducedLiverFibrosis1

1.NingJin,MS,

2.JieDeng,PhD,

3.TamunaChadashvili,PhD,

4.YueZhang,BS,

5.YangGuo,MD,

6.ZhuoliZhang,MD,

7.Guang-YuYang,MD,PhD,

8.ReedA.Omary,MDand

9.AndrewC.Larson,PhD

+AuthorAffiliations

1.1FromtheDepartmentsofRadiology（N.J.,J.D.,T.C.,Y.Z.,Y.G.,Z.Z.,R.A.O.,A.C.L.）,BiomedicalEngineering（N.J.,J.D.,R.A.O.,A.C.L.）,andPathology（G.Y.Y.）,andRobertH.LurieComprehensiveCancer（R.A.O.,A.C.L.）,NorthwesternUniversity,737NMichiganAve,Suite1600,Chicago,IL60611;DepartmentofMedicalImaging,Children’sMemorialHospital,Chicago,Ill（J.D.）;andDepartmentofBioengineering,UniversityofIllinoisatChicago,Chicago,Ill（Y.Z.）.

1.Addresscorrespondenceto

A.C.L.（e-mail:

a-larson@northwestern.edu）.

1.Authorcontributions:

Guarantorsofintegrityofentirestudy,Z.Z.,A.C.L.;studyconcepts/studydesignordataacquisitionordataanalysis/interpretation,allauthors;manuscriptdraftingormanuscriptrevisionforimportantintellectualcontent,allauthors;manuscriptfinalversionapproval,allauthors;literatureresearch,N.J.,J.D.,T.C.,Y.Z.,Y.G.,Z.Z.,A.C.L.;experimentalstudies,allauthors;statisticalanalysis,N.J.,J.D.,Y.Z.,Y.G.,Z.Z.;andmanuscriptediting,N.J.,J.D.,Y.Z.,Y.G.,Z.Z.,G.Y.Y.,A.C.L.

NextSection

Abstract

Purpose:

Toinvestigatetherelationshipbetweengas-challengebloodoxygenlevel–dependent（BOLD）magneticresonance（MR）imagingmeasurementsandhepaticdiseaseprogressioninaratmodelofdiethylnitrosamine（DEN）-inducedliverfibrosis.

MaterialsandMethods:

Theinstitutionalanimalcareandusecommitteeapprovedallexperiments.Liverfibrosiswasinducedin27maleWistarratsbymeansofweeklyoralgavagewith5mLof1.5%DENsolutionperkilogramofbodyweightfor3–11weeks,whichproducedvaryingdegreesofliverfibrosis.Eightratsdevelopednonsubstantialfibrosis（非物质性的纤维化）;eightrats,substantialfibrosis;and15rats,cirrhosis（肝硬化）.Fournontreatedhealthyratsservedascontrols.Multiple-gradient-echoMRimageswereacquiredintheratsatsteady-statenormoxiaandhyperoxiaandthenduringdynamicgaschallenges.ThechangeinR2（麻醉第二期）*（ΔR2*）duringthegaschallengeandtheratioofnumberofactivatedvoxels（三位像素）tototalnumberofvoxelsintheliverwerequantified（数量确定）.Massontrichromestaining（三色这色）oflivertissuewasusedtoidentifycollagen（胶原蛋白）tissue.Liverfibrosiswasassessedbyusingasemiquantitative（半定量）METAVIRscoringsystemandquantitativeanalysisofthepercentageofliverfibrosis.Hepatichemodynamic（血液动力学）responsesatBOLDMRimagingwerecomparedacrossthefibrosisstagesatindependent（自变量）-samplettestandlinearregressionanalyses.

Results:

ΔR2*waswellcorrelatedwithgas-challengeinterval（时间间隔）.MeanΔR2*decreasedduringliverfibrosisprogression,from19.60sec−1±4.47（standarddeviation）inanimalswithoutsubstantialfibrosisto14.02sec−1±2.88and6.26sec−1±7.40inanimalswithsubstantialfibrosisandcirrhosis,respectively（P=.006forratswithoutvsratswithsubstantialfibrosis,P=.001forratswithsubstantialfibrosisvsratswithcirrhosis,P<.001forratswithoutsubstantialfibrosisvsratswithcirrhosis）.MeanΔR2*（r=−0.773）andliveractivation（r=−0.691）wereinversely（相反的）correlatedwithliverfibrosis（P<.001）.

Conclusion:

Carbogen（卡铂金）gas-challengeBOLDMRimagingcandepicthepatichemodynamicalterationsduringtheprogressionoffibrosisandhasthepotentialtoserveasanoninvasive,nonenhancedimagingmethodforliverfibrosisdiagnosisandstaging.

©RSNA,2010

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Introduction

Liverfibrosisinvolvestheexcessiveaccumulationofextracellularmatrixproteinsaspartofthewound-healingresponsetochronicliverinjury

（1）.Themaincausesofliverfibrosisarechronicviral（病毒的）hepatitistypeB,chronicviralhepatitistypeC,andalcoholabuse

（2）.Advancedliverfibrosiscanleadtocirrhosis,liverfailure,portal（入口）hypertension,andlivercancer,anditoftenrequireslivertransplantationasalife-savingprocedure.

Liverbiopsy（活检）isconsideredthereferencestandardforthediagnosisandstagingofliverfibrosis.However,itisinvasive,withassociatedpainandmajorcomplicationsreportedlyoccurringin40.0%and0.5%ofpatients,respectively（3）.Samplingerrorscanoccurowingtotheheterogeneous（混杂的，多种多样的）distributionoffibrosisintheliverandtherelativelysmallbiopsysamples（4,5）.Intra-andinterobserver（观察者之间）variationsinhistologic（组织学）examinationscanalsoleadtodiagnosiserror（6,7）.Liverfibrosismaybereversible（可逆的）whenthecauseisidentifiedandtreated（8–10）.Analternativenoninvasivediagnosisandstagingmethodwouldbeparticularlyusefulforserial（连续的）evaluationoftheeffectivenessofliverfibrosistherapies.Magneticresonance（MR）elastography（11）,diffusion-weightedMRimaging（12）,ultrasonographicperfusionmeasurements（13）,transientsonoelastography（14）,anddynamiccontrastmaterial–enhancedMRimagingandcomputedtomography（15）havebeenproposedasnoninvasivemethodsofdiagnosingandstagingliverfibrosis.

Quantitativedynamiccontrast-enhancedimaging（ie,contrast-enhancedimaging）approachesinvolvepharmacokineticanalysisofthepassageofexogenouscontrastmaterialtracers（16）.Thesemethodsofferthepotentialtodetectandcharacterizethehepaticperfusionchangesthataccompanytheprogressionofliverfibrosis（15）.Approximatelythree-quartersofthebloodinthenormalliverissuppliedfromtheportalvein,andonlyaboutone-quarterofthebloodissuppliedfromthehepaticartery（17）.Duringtheevolutionofhepaticfibrosis,theprogressivedisruptionofthenormalliverstructureleadstobothregionalandglobalperfusionchanges.Portalvenousflowtypicallydecreasesandbypassestheliverparenchymaviaportosystemicvenousshunts,whilehepaticarterialflowmayincreasetocounteracttheeffectofthereducedportalvenousflow.Thiscounteractiveincreaseinhepaticarterialflowiscommonlyreferredtoasthehepaticarterialbufferresponse（18,19）.Quantitativecontrast-enhancedimagingmethodscanbeusedtoresolveeachcomponentofthedualbloodsupplyintheliver（20）.Initialpreclinicalandclinicalfeasibilitystudieshaverevealedthepotentialtousethesedifferentialbloodflowmeasurementstocharacterizediseaseprogression（21–23）.

Bloodoxygenlevel–dependent（BOLD）MRimagingisanalternativeimagingtechniquethatinvolvestheuseofdeoxyhemoglobinasanendogenouscontrastmechanismtoreflectalterationsinbloodoxygenation,bloodflow,andbloodvolume.AlthoughBOLDMRimagingmethodsarewidelyusedforfunctionalactivationstudiesofthebrain（24,25）,theyareincreasinglybeingusedforfunctionalimagingoftumors（26）,cardiac（27）andskeletal（28）muscle,renaltissue（29）,andtheliver（30）.BOLDMRexaminationsofratlivertissuehaverevealedsubstantialincreasesinsignalintensityatT2*-weightedimagingduringhyperoxiainducedbycarbogengas（95%O2,5%CO2）inhalation（30）,andmorerecentstudiesinvolvingtheuseofa4.7-Tspectrometerinfibroticmouselivertissuehaverevealedareducedresponseatgas-challengeT2*-weightedBOLDimagingcomparedwiththisresponseinhealthycontrolanimals（31）.Gas-challengeBOLDMRimaginghasthepotentialtoserveasanoninvasive,nonenhancedmethodofcharacterizinghemodynamicprocessesoftheliver.Thepurposeofourstudywastoinvestigatetherelationshipbetweengas-challengeBOLDMRimagingmeasurementsandhepaticdiseaseprogressioninaratmodelofdiethylnitrosamine（DEN）-inducedliverfibrosis.

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MaterialsandMethods

AnimalModel

AllexperimentswereapprovedbytheinstitutionalanimalcareandusecommitteeofNorthwesternUniversityandwereperformedinaccordancewithinstitutionalguidelines.Thirty-oneadultmaleWistarrats（Harlan,Indianapolis,Ind）thatinitiallyweighed300–350gwereusedfortheexperiments.Theratswererandomlydividedintocontrolandtreatmentgroups.Fournontreatedhealthyratswereusedascontrolanimals.Twoauthors（N.J.,2yearsexperience;Y.G.,1yearofexperience）inducedliverfibrosisin27ratsbymeansofweeklyoralgavagebyusingan18-gaugegavageneedletoinject5mLof1.5%DENsolution（DENISOPAC;SigmaChemical,StLouis,Mo）perkilogramofbodyweight.

MRMeasurements

AllMRimagingexaminationswereperformedbyusinga3.0-TclinicalMRunit（MagnetomTrio;SiemensMedicalSolutions,Erlangen,Germany）withacustom-builtrodentreceivercoilthathadaninnerdiameterof7cm（ChenguangMedicalTechnologies,Shanghai,China）.Beforebeingimaged,theratswereanesthetizedwithanupper-limbinjectionofketamine（Ketaset,75–100mgperkilogramofbodyweight;FortDodgeAnimalHealth,FortDodge,Iowa）andxylazine（Isothesia,2–6mg/kg;AbbottLaboratories,NorthChicago,Ill）.Theabdomenofeachratwasfixedwithadhesivetapetorestrictrespiratorymovement.

CoronalandtransverseT2-weightedturbospin-echoMRimages（4500/61[repetitiontimemsec/echotimemsec],140°flipangle,threeacquiredsignals）oftheentireabdomenwereacquiredforlocalization.ThreeadjacenttransversesectionsthroughthecentralportionoftheliverwerechosenfortheBOLDMRexaminations.TheresponseatBOLDMRimagingwasevaluatedbyusingquantitativeR2*measurements,whichwereobtainedbyusingamultiple-gradient-echosequence（150-msecrepetitiontime,echotrainlengthofnine,4.6-msecintersectionspacing,30°flipangle,3-mmsectionthickness,150-mmfieldofview,192×76matri