1.2LiverBiopsy:AdvantagesandInconveniences
Histologicalstagingof fibrosisisacombinatorialassessmentofamountof fibrosis andarchitecturaldisorganization,basedonsemi-quantitativescoringsystems, includingthehistologicalactivityindex[7],theIshakscore[8],andtheMETAVIR scoringsystem[9].Simultaneousevaluationofnecro-inflammation(portaltract inflammation,interfacehepatitis,lobularinflammation)assesseswhether fibrosisis theresultofapasteventthathasstabilizedorevenregressedorisanongoing processthatmaycontinuetoworsen.Finally,apartfrom fibrosis,liverbiopsyalso detectsassociatedlesionssuchassteatosis,steato-hepatitis,ironoverload,and alcohol,whichprovideusefulinformationforpatientmanagementand prognosis[10].
Liverbiopsyhashoweverwell-knownlimitations:itisaninvasiveprocedure associatedwithtransientpain,anxiety,anddiscomfortinaround30%ofcases[11–13]andrarebutpotentiallylife-threateningcomplications(hemorrhagein0.3%of casesandmortalityin0.01%)[14].Performingofbiopsybyatrainedphysician,use ofonlyalimitednumberofpasses,andultrasoundguidancecansignificantly decreasetheriskofcomplications,therebyenhancingthesafetyofbiopsy.
Theaccuracyofliverbiopsytoassess fibrosishasalsobeenquestioned,in relationtosamplingerrorsandintra-andinter-observervariabilitythatmaylead toover-orunder-staging.Thesizeofthebiopsyspecimen,whichvariesbetween 10and30mminlengthandbetween1.2and2mmindiameter,represents1/50,000 ofthetotalmassoftheliverandsocarriessubstantialsamplingerror.Increasingthe lengthofliverbiopsydecreasestheriskofsamplingerror[15].However,cirrhosis maybemissedonasingle-blindliverbiopsyin10to30%ofcases[16].Finally, apartfromthecharacteristics(samplesize)oftheliverbiopsy,thedegreeof experienceofthepathologist(specialization,durationofpractice,andacademic practice)mayalsohaveaninfluenceoninter-observeragreement[17].
Exceptforcirrhosis,forwhichmicro-fragmentsmaybesufficient,a25-mm-long biopsyisconsideredanoptimalspecimenforaccurateevaluation,though15mmis consideredsufficientinmoststudies[18].Inclinicalpractice,liverbiopsyshould alwaysbeperformedonlyaftercarefullybalancingrisksoftheprocedurewith potentialbenefitsintermsofpatientmanagement.
1.3CurrentlyAvailableNon-invasiveMethods
1.3.1BiologicalApproach:SerumBiomarkersofLiverFibrosis
Manyserumbiomarkersandevaluatedfortheirabilitytodeterminestageofliver fibrosisinpatientswithchronichepatitisC[19–34].Theyaresummarizedin Table 1.1:someareproprietaryalgorithmsliketheFibroTest®,whileothersare non-proprietaryformula,usingpublishedmodels,basedonroutinelyavailable laboratorytests.
Table1.1 Currentlyavailableserumbiomarkersfornon-invasiveevaluationofliver fibrosisin chronichepatitisC(adaptedfromref.[4])
• FibroTest® (Biopredictive,Paris,France)patentedformulacombining α-2-macroglobulin, γGT,apolipoproteinA1,haptoglobin,totalbilirubin,age,andgender
• Fornsindex ¼ 7.811 3.131 ln(plateletcount)+0.781 ln(GGT)+3.467 ln (age) 0.014 (cholesterol)
• ASTtoplateletratio(APRI) ¼ AST(/ULN)/platelet(109/L) 100
• FibroSpectII® (PromotheusLaboratoryInc,SanDiego,USA)patentedformulacombining α-2-macroglobulin,hyaluronate,andTIMP-1
• MP3 ¼ 0.5903 logPIIINP(ng/ml) 0.1749 logMMP-1(ng/ml)
• EnhancedLiverFibrosis(ELF)score® (SiemensHealthcare,Erlangen,Germany)patented formulacombiningage,hyaluronate,MMP-3,andTIMP-1
• Fibrosisprobabilityindex (FPI) ¼ 10.929+(1.827 LnAST)+(0.081 Age)+(0.768 pastalcohol usea)+(0.385 HOMA-IR) (0.447 cholesterol)
• Hepascore® (PathWest,UniversityofWesternAustralia,Australia)patentedformula combiningbilirubin, γGT,hyaluronate, α-2-macroglobulin,age,andgender
• Fibrometers® (Echosens,Paris,France)patentedformulacombiningplateletcount, prothrombinindex,AST, α-2-macroglobulin,hyaluronate,urea,andage
• Lokindex ¼ 5.56 0.0089 platelet(103/mm3)+1.26 AST/ALTratio ¼ 5.27 INR
• GotebörgUniversityCirrhosisIndex(GUCI) ¼ AST prothrombin-INR 100/platelet
• Virahep-Cmodel ¼ 5.17+0.20 race+0.07 age(years)+1.19ln(AST [IU/L]) 1.76ln(plateletcount[103/mL])+1.38ln(alkalinephosphatase[IU/L]
• Fibroindex ¼ 1.738 0.064 (platelets[104/mm3])+0.005 (AST [IU/L])+0.463 (gammaglobulin[g/dl])
• FIB-4 ¼ age(years) AST[U/l]/(platelets[109/l] (ALT[U/l])1/2
• HALT-Cmodel ¼ 3.66 0.00995 platelets(103/mL)+0.008 serumTIMP1+1.42 log(hyaluronate)
aGradedas0–2
Thepracticaladvantagesofanalyzingserumbiomarkerstomeasure fibrosis includetheirhighapplicability(>95%)andinter-laboratoryreproducibilityand theirpotentialwidespreadavailability(Table 1.2).However,noneareliverspecific theirresultscanbeinfluencedbycomorbidextra-hepaticconditions,andthey requirecriticalinterpretationofresults.
1.3.2PhysicalApproach:MeasuringLiverStiffness
1.3.2.1TransientElastography
Transientelastography(TE)wasthe firstcommerciallyavailableultrasound-based elastographymethoddevelopedforthemeasurementofliverstiffness,usinga dedicateddevice(FibroScan®,Echosens,Paris,France)[35].TEmeasures thevelocityofalow-frequency(50Hz)elasticshearwavepropagatingthrough theliver,whichisdirectlyrelatedtotissuestiffness;thestifferthetissue,thefaster theshearwavepropagates.Theexaminationisperformedontherightlobeofthe liverthroughtheintercostalspace.Themeasurementdepthisbetween25and65mm usingtheMprobe(standardprobe)andbetween35and75mmusingtheXLprobe.
Table1.2 Respectiveadvantagesanddisadvantagesofcurrentlyavailablenon-invasivemethodsinpatientswithchronichepatitisC(adaptedfromref[
Measurementofliverstiffness
TransientelastographyARFI2DSWEMRelastography
• Canbe implementedona regularMRI machine
• Examination ofthewholeliver
• Higher applicabilitythan TE
• High performancefor cirrhosis
• Canbeimplemented onaregular
• Canbeimplemented onaregularUSmachine
• Mostwidelyusedandvalidated technique:standardtobebeaten
• USmachine
• ROIcanbeadjustedin sizeandlocationandchosen bytheoperator
• Real-time measurement
• Highrangeofvalues (2 –150kPa)
• Goodapplicability
• Performance equivalenttothatofTEfor signi fi cant fi brosisand cirrhosis
• ROIsmallerthanTE butlocationchosenbythe operator
• Higherapplicability thanTE(notlimitedby ascitesorobesity)
• Performance equivalenttothatofTEfor signi fi cant fi brosisand cirrhosis
• User-friendly(performedat bedside;rapid,easytolearn)
• Highrangeofvalues(2 –75kPa)
• Qualitycriteriawellde fi ned
• Goodreproducibility
• Highperformanceforcirrhosis (AUROC > 0.9)
• Prognosticvalueincirrhosis
Serumbiomarkers
Advantages
• Good reproducibility
• Highapplicability (95%)
• Nocostandwide availability (non-patented)
• Wellvalidated
• Canbeperformed intheoutpatientclinic
• Requiresa MRIfacility
• Lesswell evaluatedthanTE
• Unabletodiscriminate betweenintermediatestages of fi brosis
• Unabletodiscriminate betweenintermediatestages of fi brosis
• Requiresadedicateddevice
• ROIcannotbechosen
• Morecostly andtime- consumingthanTE
• Failuredueto claustrophobiaor ironoverload
• Qualitycriterianot wellde fi ned
• Units(m/sec)different fromthatofTE(kPa)
• Unabletodiscriminatebetween intermediatestagesof fi brosis
• Lesswellvalidated thanTEandARFI
• Narrowrangeofvalues (0.5 –4.4m/sec)
• Applicability(80%)lowerthan serumbiomarker:(obesity,ascites, operatorexperience)
• Qualitycriterianot wellde fi ned
• Falsepositiveinthecaseofacute hepatitis,extra-hepaticcholestasis, livercongestion,foodintake,and excessivealcoholintake
Disadvantages
• Non-speci fi cofthe liver
• Unableto discriminatebetween intermediatestagesof fi brosis
• Performancenotas goodasTEforcirrhosis
• Costandlimited availability(proprietary)
• Limitations (hemolysis,Gilbert syndrome, in fl ammation ... )
Assuggestedbythemanufacturer,tensuccessfulacquisitionsshouldbeperformed oneachpatient.Themedianofthesemeasurementsisdisplayedandusedfor interpretation.Resultsareexpressedinkilopascals(kPa)andrangefrom1.5to 75kPawithanormalvaluearound5kPa[36].
AdvantagestoTEincludethefactthatitisawidelyavailablepoint-of-care technique,withashort-timeprocedure(<5min)andimmediateresults,thatcan beperformedintheoutpatientclinicbyanurseafterashortlearningcurve (Table 1.2).Qualitycriteriaarewelldefined,basedonatleasttenvalidated measurementsandaninterquartilerange(IQR,reflectsvariationsamong measurements)oflessthan30%ofthemedianvalue(IQR/LSM 30%)[37].It hasbeensuggestedthatanevenlowerinterquartilerangeshouldbeused,especially innon-Asianpatientswithadvanced fibrosis,butthesecriteriahavenotbeen independentlyvalidated[38].
AlthoughTEanalysishasexcellentinter-andintra-observeragreement[39],its applicability(80%),whenusingtheMprobe[40],isnotasgoodasthatofserum biomarkers.Thetwomainfactorsassociatedwithdecreasedapplicabilityareobesity andlimitedoperatorexperience.TheuseoftheXLprobehasbeenproposedto overcometheselimitationsandhasbeenshowntoincreaseapplicabilitytomore than95%inobesepatients[41].
Thereareseveralconfoundingfactors,suchastransaminases flares,acutehepatitis,extra-hepaticcholestasis,orcongestion,whichmayleadtooverestimationof liverstiffnessmeasurements,independentof fibrosis.Finally,foodintakehasbeen showntobeassociatedwiththeriskofoverestimatingliverstiffnessvalues [42, 43].Therefore,TEshouldbeperformedinpatientsfastingforatleast 2hours[4].
Insummary,TEneedstobeperformedusingastandardizedprotocolandwith criticallyinterpretedresults,takingconfoundingfactorsintoaccount.
1.3.2.2OtherImagingMethods
Severalotherelastographytechniqueshavebeendeveloped,eitherultrasound-based suchaspointshearwaveelastography/acousticradiationforceimpulse(pSWE/ ARFI)imagingand2Dshearwaveelastography(2DSWE)ormagnetic resonance-basedsuchasMRelastography(MRE)[44].
pSWE/ARFItechniques,integratedinconventionalultrasoundsystems,use focusedUS “push” pulsestodeforminternaltissueandgenerateshearwaves. OriginallyavailableinSiemenssystems(VirtualTouchQuantificationTM Acuson 2000,SiemensHealthineers,Erlangen,Germany),pSWE/ARFImethodsarenow integratedintotheirclinicalultrasoundsystemsbymostvendors[45].Regionof interest(ROI)localizationcanbechosenunderBmodevisualization.Asingle acousticimpulseisusedtoinduceashearwavewithinasmallROI(approximately 1.0 0.5cm),andthevelocityofshearwavesismeasuredinmeter/secorkPa. 2DSWE,likepSWE/ARFI,isintegratedinconventionalultrasonography systems,enablingtheadditionalperformanceofelastographywiththesameprobes asabdominalultrasound.OriginallyavailableclinicallyinSuperSonicImagine system(AixplorerTM,SupersonicImagine,Aix-en-Provence,France),2DSWEis
nowintegratedintheirsystemsbyseveralvendors.Multipleshearwavesare inducedusingacousticimpulses.ThesizeoftheROIcanbeincreasedtoapproximately2 2cmandshownaseithersingleimageorinrealtime.Velocityof stiffnesscanthenbemeasuredatvaryinglocationswithinthisROI,andstatistical quantitiessuchasthemean,standarddeviation,andminimumandmaximumvalues ofthe2DSWEorYoung’smodulusinkPaarecalculatedanddisplayed[44].
ThemajoradvantageofpSWE/ARFIandSWEisthattheycanbeperformedon commercialultrasoundmachineswithoneprobeinallpatients,independentofbody weight,astheROIcanbepositionedmanuallyatdifferentdepthsintheliver (Table 1.2).However,thesetechniquesalsorequiremoreoperatortrainingand expertise.QualitycriteriafortheperformanceandinterpretationofpSWE/ARFI and2DSWEarenotwelldefinedbythemanufacturers.
TheadvantagesofMREincludeitsabilitytoanalyzealmosttheentireliverand itsapplicabilitytopatientswithobesityorascites.Failurerateisindeedlow(6%) andiscausedbyclaustrophobia,lowhepaticsignalrelatedtoironoverload,ornot fittingintotheMREmachineowingtoobesity.However,MREistoocostlyand time-consumingtobeusedinroutinepracticeandismoresuitedforresearch.
1.4DiagnosticPerformancesofNon-invasiveMethods forStagingLiverFibrosis
1.4.1Endpoints
Twoclinicallyrelevantendpointshavebeenwidelyusedintheliteraturetoevaluate non-invasivemethods:(1)Detectionofsignificant fibrosis(METAVIR,F 2or Ishak, 3),whichisanindicationforantiviraltreatmentinchronichepatitis C.However,withtheavailabilityofDAAabletoachievesustainedvirological response(SVR)ratesabove90%withlimitedsideeffects,significant fibrosisno longerrepresentanimportantdecision-makingendpointinHCV-infectedpatients. (2)Detectionofcirrhosis(METAVIR,F4orIshak,5–6),whichisanindicationfor speci ficmonitoringofcomplicationsrelatedtoportalhypertensionandtothe increasedriskofdevelopinghepatocellularcarcinoma(HCC)[46, 47].
1.4.2SerumBiomarkersofFibrosis
Diagnosticperformancesforsigni ficant fibrosisandcirrhosisofthedifferent biomarkersaresummarizedinTable 1.3.Todate,FibroTest®,APRI,andFIB-4 havebeenthemostextensivelystudiedinpatientswithchronichepatitisC.Ina meta-analysisfromthedeveloper[48],whichpooled6,378subjects(withanalysisof individualdatain3,282)withbothFibroTest® andbiopsy(3,501HCV,1,457HBV, 267NAFLD,429ALD,and724mixed),themeanstandardizedAUROCfor diagnosingsigni ficant fibrosiswas0.84(95%CI,0.83–0.86),withoutdifferences betweencausesofliverdisease.Anothermeta-analysis[49]analyzedresultsfrom
6259HCVpatientsfrom33studies;themeanAUROCvaluesfromtheAPRIin diagnosisofsignificant fibrosisandcirrhosiswere0.77and0.83,respectively.When comparedandvalidatedexternallyinpatientswithviralhepatitis(n ¼ 1307patients withviralhepatitis)[50],thedifferentpatentedscores(FibroTest®,Fibrometre®, Hepacore®)andnon-patentedscores(APRI)hadsimilarperformancesforthe diagnosisofsigni ficant fibrosis(AUROCsrangingfrom0.72to0.78)andcirrhosis (AUROCSrangingfrom0.77to0.86).Non-patentedscoresarecost-free,easyto calculate,andavailablealmosteverywhere.
1.4.3TransientElastography
Thetwoindexstudies[51, 52],suggestingtheinterestofTEfortheassessmentof liver fibrosis,havebeenconductedinpatientswithchronichepatitisC,andtheir resultshavebeenconfirmedbymanyothergroupssince[50, 53–56](Table 1.4). Severalmeta-analyses[57–61]haveshownthebetterdiagnosticaccuracyofTEfor cirrhosis(AUROCs0.93–0.96)thanforsigni ficant fibrosis(AUROCs0.84–0.87). However,ameta-analysisbasedonindividualdataisstillawaited.Thediagnostic accuracyofTEisconsideredexcellentforthediagnosisofcirrhosiswithsensitivities andspeci ficitiesof83–87%and89–95%,respectively.Actually,TEisbetterat rulingout,ratherthanrulingin,livercirrhosis(withnegativepredictivevaluehigher than90%).Differentcutoffshavebeenproposedfordifferentliverdiseases, dependingonthedistributionof fibrosisstagesindifferentcohorts,butnoconsensus hasbeenreached.Inthemeta-analyses,cutoffsrangedfrom7.3to7.9kPaforthe diagnosisofsignificant fibrosisandfrom13.0to15.6kPaforthediagnosisof cirrhosis[58, 60–62].However,thecutoffchoicemustalsoconsiderthepre-test probabilityofcirrhosisinthetargetpopulation(varyingfrom <1%inthegeneral populationto10–20%intertiaryreferralcenters).Forexample,ithasbeenshown thatinapopulationwithapre-testprobabilityof13.8%,cirrhosisprobabilityata cutoff <7kParangedfrom0to3%,whereasatacutoff >17kPa,cirrhosis probabilitywas72%[50].Thus,observerexperience,patientfactors,diseaseetiology,aswellaspre-testprobabilityofcirrhosisshouldbetakenintoaccountwhen measurementvaluesareinterpreted.
1.4.4OtherImagingMethods
pSWE/ARFIperformancehasbeenevaluatedinthreemeta-analysesreporting diagnosticaccuraciesof84–87%forthediagnosisofsignificant fibrosisandof 92–93%forthediagnosisofcirrhosis[63–65].Cutoffsrangedfrom1.34to1.35m/ sforsignificant fibrosisand1.80to1.87m/sforcirrhosis.Itshouldbestressed howeverthatmoststudiesincludedinthesemeta-analyseswerebasedonsmall samplesofheterogeneouspopulationsanddidnotalwaysuseliverbiopsyas reference.ThissaidpSWE/ARFIlikeTEisbetteratrulingoutthanrulinginliver cirrhosis.Anothermeta-analysiscomparingpSWE/ARFIwithTEreported
Table1.3 Diagnosticperformanceofserumbiomarkersof fi brosisforsigni fi cant fi brosis(F 2)andcirrhosis(F4)inpatientswithchronichepatitisC
BiomarkersYearPatients( n )F 2(%)F4(%)CutoffsAUROCSe(%)Sp(%)CC(%)
–9451 –9545
FibroTest ® [ 22 ]200133980 >
Fornsindex[ 23 ]200247626
24 ]20032705017
–
–6585 –96NA
FibroSpectII ® [ 25 ]200469652 >
26 ]20041944522 a
® [ 27 ]20041021/496 b 40120.102
Fibrometer ® [ 30 ]2005598/503 b
0.80.7742 –8548 –9840 –49 Hepascore ® [ 29 ]20052115716
FPI[ 28 ]200530248
Lokindex[ 31 ]2005114138 < 0.2 0.50.8140 –9853 –9952 GUCI[ 32 ]200517912 > 0.10.858070NA ViraHep-C[ 33 ]200639837 0.22 > 0.550.8351 –9054 –9052
Fibroindex[ 34 ]200736050 1.25 2.250.8330 –4097 –9735 FIB-4[ 35 ]200783017 a < 1.45 > 3.250.8538 –7481 –9868
HALT-Cmodel[ 36 ]200851238 < 0.2 0.50.8147 –8845 –9248
AUROC:areaunderROC:curve;Se:sensitivity;Sp:speci fi city;CC:correctlyclassi fi ed:truepositiveandnegative;NAnotavailable a F3F4 b HCVpatients
Table1.4 DiagnosticperformanceofTEforsignificant fibrosis(F 2)andcirrhosis(F4)in patientswithchronichepatitisC
AuthorsYear
Castera etal.[53]
Zarski etal.[58]
AUROC:areaunderROCcurve;Se:sensitivity;Sp:specificity;CC:correctlyclassified:true positiveandnegative aValidationcohort:HCV92%;HBV8%
comparablesensitivitiesandspeci ficitiesfortheassessmentofliver fibrosis [66].Thus,atpresent,pSWE/ARFIcanbeusedwithequivalentresultstoTE.
2DSWEhasbeenevaluatedinonlyafewstudies,showingcomparableoreven superiorresultstoTEforthediagnosisofsignificant fibrosisandcomparableresults forthediagnosisofcirrhosis[67, 68].Ameta-analysis,basedonindividualdatain 1,340patientswithchronicliverdisease,reporteddiagnosticaccuraciesof86%for thediagnosisofsignificant fibrosisand95%forcirrhosis[69].Theoptimalcutoffs were7.1and13.5kPa,respectively.Again,2DSWEisalsobetteratrulingoutthan rulinginlivercirrhosis.Whencomparing2DSWEtoTEinthismeta-analysis,no significantdifferencewasfoundbetweenthetwomethodsifthequalitycriteriaof TEwererespected.
Studiescomparingallthreemethods(TE,pSWE/ARFI,and2DSWE)inthe samepatientpopulationreportedatleastcomparableresultsforallthreemethods withaslightsuperiorityof2DSWEforintermediate fibrosisstages[70, 71].Thus,at present,2DSWEcanalsobeusedwithequivalentresultstoTE.
AsforMRE,meta-analysesreporteddiagnosticaccuraciesof93–98%forthe diagnosisofadvancedliver fibrosis(F 3)withsensitivitiesof85–92%and speci ficitiesof85–96%,respectively[72, 73].Alimitednumberofstudieshave directlycomparedMREtoTEonsmallsampledheterogeneouspopulationsand withconflictingresults:onestudyreportedcomparable[74],whereasotherreported superiorresultsofMREtoTE[75, 76].However,thewidespreaduseofthismethod willdependoncostandavailability.
1.5.1BeforeStartingAntiviralTreatment
TheEASLclinicalpracticeguidelinesrecommendthatallpatientswithchronic hepatitisCshouldbeassessedforliverdiseaseseveritybeforeantiviraltherapyusing analgorithmcombiningnon-invasivetests(TEandserumbiomarkers)[4](Fig. 1.1). Thisstrategyhasbeenvalidatedinclinicalpractice[77, 78].Identifyingpatients withcirrhosisoradvanced(bridging) fibrosisisofparticularimportance,asthe choiceofthetreatmentregimenwithnovelDAAagentsandthepost-treatment prognosisdependonthestageof fibrosis.Inpatientswithvaluesintherangeofliver cirrhosis,screeningforportalhypertensionandhepatocellularcarcinoma(HCC)is alsorecommendedwithoutpriorliverbiopsy[46, 47].Inthecaseofunexplained discordanceorsuspectedadditionaletiologiesofliverdisease,aliverbiopsyisstill recommended[4].
1.5.2DuringAntiviralTreatment
Amajoradvantageofnon-invasivetests,comparedwithliverbiopsy,isthattheycan beeasilyrepeatedovertimeinpatientsreceivingantiviraltherapyandthatthey couldbeusedtomonitorresponsetotreatmentandtoevaluate fibrosisregression. However,thechanginglevelsofALTandinflammationofsuccessfullytreatedHCV patientscanconfoundresultsofTEorbiomarkers.Indeedinamulticenterprospectivestudy[79]thatassessedliverstiffnesskineticsatmultipletimepointsduring therapy(week4and12)andafterward(week24),liverstiffnessdecreasedsignificantlywithtreatmentamongpatientswhodidanddidnotachievesustainviral eradication.Theseresultssuggestthatthemajorcomponentofthesigni ficant decreaseobservedinliverstiffnessvaluesisnotjustreversalof fibrosisbutalso reductioninliverinjury,edema,andinflammation.Alsosignificantvariabilityof liverstiffnessmeasurements,notrelatedtodiseaseprogressionorregressionbut rathertooperatorexperienceandpatientsBMI,hasbeenreported[80].Thus, monitoringliverstiffnessorserumbiomarkersduringantiviraltreatmentisof limitedclinicalvalueandthereforenotrecommended[4].
1.5.3AfterAntiviralTreatment
Severalstudiesreportedasigni ficantdecreaseinliverstiffnessandbiomarkers values,comparedwithbaselinevalues,inHCVpatientswhoachievedSVR [79, 81–91],consistentwithsigni ficanthistologicimprovementdocumentedin studiesofpairedliverbiopsiesinthesepatients[92, 93].Itshouldbestressed howeverthatthesestudiessufferfromseveralmethodologicalshortcomings:most areretrospective,withsmallsamplesize,includingpatientsmainlytreatedwith interferon-basedtherapieswithashortfollow-upandnopairedliverbiopsies.
HepatitisC
Treatment-naive
Combine
Twonon-invasive tests:
TE + serumbiomarker
Discordance
Repeatexams and searchfor explanations
Discordance
Liver biopsy if results influence management
No severefibrosiscirrhosis
Concordance
Severefibrosiscirrhosis
No liverbiopsy
Follow-up or antiviral treatment (if extra-hepaticmanifestations)
No liver biopsy
Antiviral treatment Screening for Varices Screening for HCC
Fig.1.1 Algorithmfortheuseofnon-invasivetestsintreatment-naivepatientswithhepatitisC (adaptedfromref.[4])
Nevertheless,inarecentmeta-analysis[94],basedon24studies(10withDAA) includingatotalof2934HCVpatients,SVRwasassociatedwithasignificant decreaseinliverstiffness,particularlyinpatientswithhighbaselinelevelofinflammationorpatientswhoreceivedDAA.Almosthalfthepatientsconsideredtohave advanced fibrosis,basedonTE,beforetherapyachievedpost-treatmentliverstiffnesslevels <9.5kPa.
Therearetwoimportantclinicalquestionsabouttheuseofnon-invasivetests afterantiviraltreatment.Firstwhatistheevidenceof fibrosisandparticularly cirrhosisreversalbynon-invasivetests?Thereversalofcirrhosishasimportant consequencesinthatitmayalterlong-termprognosisparticularlyforHCCoccurrenceinHCVpatientsandchangetheapproachtoscreeningforHCCafterSVR [95, 96].Thisleadsintothesecondquestion,whichiswhatisthecutoffthresholds post-SVRfordeterminationofdecreasedriskofliver-relatedoutcomes?Inastudy thathasexaminedreversalofcirrhosisin33HCVpatientswithcirrhosiswithpreandpost-treatmentliverbiopsiesandTEafterSVR[97],therewasreversalof cirrhosisbybiopsyin19patientswith11ofthe19beingMetavirF3andthe remainderF1orF2.Usingacutoffof12kPa,TEhadasensitivityof61%anda speci ficityof95%.ThelowsensitivitymakesTEapoortooltobeutilizedclinically asevidenceofcirrhosisregression.Finally,thebesttimingforrepeatedassessment
ofliverstiffnessaftertherapyhasnotbeenestablishedyet.Inanotherstudy[98] fromthesamegroupin38HCVpatientswithcirrhosiswithpre-andpost-treatment liverbiopsiesandserumbiomarkers(APRI,FIB-4,Fornsscore,GUCI,Kingscore, LokIndex,andELF)afterSVR,noneofthesetestshelpedinpredictingresidual fibrosis.Therefore,liverbiopsyremainsthegoldstandardforthispurpose,and routineuseofnon-invasivetestsafterSVRinpatientswithoutcirrhosisisnot recommended,asitdoesnotchangeclinicaldiseasemanagement[4].Inpatients withcirrhosis,regressionof fibrosiswouldimproveoutcome;however,highfalsenegativeratesofnon-invasivetestshavebeenreportedthatdonotjustifyareduction inHCCsurveillanceinthesepatients.
1.6MonitoringDiseaseProgressionandPrognosis
Thereissubstantialevidenceindicatingthatliverstiffness,usingTE,canbequite effectiveindetectingpatientswithahighriskofhaving(ornothaving)developed clinicallysignificantportalhypertension(CSPHdefinedbyahepaticvenouspressuregradient 10mmHg).Arecentmeta-analysis(basedon11studiesincluding 1451patients)hasconfirmedtheexcellentperformancesofTEwithahierarchical summaryAUROCof0.90andwithsensitivityandspeci ficityabove85%(sensitivity,87.5%;95%confidenceinterval[CI]:75.8–93.9%;specificity,85.3%;95%CI: 76.9–90.9%)[99].Itisestimatedthatmorethan90%ofpatientswithaliverstiffness >20–25kPawillhaveclinicallysignificantportalhypertension[100].Liverstiffness usingTEishoweverlessaccurateforthepredictionofesophagealvarices(EV)than forCSPH[101].Inarecentmeta-analysis[102](basedon18studiesand3644 patients),thediagnosticperformancesofTEforpredictingEVandlargeesophageal varices(LEV)werenotasgoodasforCSPH,withAUROCSof0.84and0.78, respectively.Althoughthesummarysensitivityforthepredictionofthepresenceof EVandLEVwashigh(0.87(95%CI:0.80–0.92);0.86(95%CI:0.71–0.94), respectively),specificitywasmuchlower(0.53(95%CI:0.36–0.69);0.59(95% CI:0.45–0.72),respectively)andlesssatisfactory.Inordertoincreasethediagnostic accuracy,scores,likeLSPS(LSM-spleendiametertoplateletratioscore),combiningliverstiffnesswithparametersassociatedwithportalhypertension,suchas plateletcountorspleendiameterbyultrasound,havebeenproposed[103, 104].In 2015,theBavenoVIconsensusonportalhypertensionproposedusingthecombinationofliverstiffnessandplateletcount(i.e.,plateletcount >150g/LandLSM <20kPa)toidentifypatientswithearlycirrhosisthatcouldsafelyavoidscreening endoscopy[105].Interestingly,theperformanceofthesecriteriahasbeenconfirmed independentlyinvariouspopulations[106–108]andintwometa-analyses [109, 110].Allstudiesconfirmedthatabout20%ofupperGIendoscopiescould besafelyavoided,missinglessthan4%ofpatientswithvaricesneedingtreatment. Theserecommendationsrepresentasigni ficantadvanceinthemanagementofHCV patientswithearlycirrhosisandcanbeconfidentlyappliedineverydaypractice.As forpSWE/ARFIand2DSWE,giventheverylimitednumberofstudiesreportingon
theirperformancefordetectionofEVandLEV,norecommendationcanbe made[100].
Theabilityofliverstiffness,measuredusingTE,orofserumbiomarkerstoalso predictclinicaldecompensationandsurvivalinpatientswithchronichepatitisChas beenshownbyseveralstudies[89, 111, 112]aswellasafterviraleradication [113].Inonestudythatlookedattheevolutionofliverstiffnessvaluesovertime in1025patientswithchronichepatitisC[89],theprognosisofpatientswithliver stiffnessvaluesbetween7and14kPaoninclusionwassignificantlyimpairedwhen anincrease 1kPa/yearwasobserved.Thus,thepotentialofliverstiffnessvalues forpredictingclinicaloutcomesseemstobegreaterthanthatofliverbiopsy; probablyliverstiffnessmeasuresongoingpathophysiologicalprocessesand functionsthatabiopsycannot.Althoughmostprognosticstudieswereperformed withTE,otherprognosticstudiesusingpointor2DSWEarecurrentlyrunning,and thefewthathavebeenpublishedreportcomparableprognosticcapabilities[114–116].
1.7Conclusions
Significantprogresshasbeenmadeoverthepastdecadeinnon-invasiveassessment ofliverdiseaseinpatientswithhepatitisC.Non-invasivetestsarenowreadyfor “primetime” toprioritizenaiveHCVpatientsforDAAtherapies.Thecombination ofTEandserumbiomarkersisnowroutinelyusedas first-lineevaluation,liver biopsybeingreservedonlyincasesofunexplaineddiscordancebetweenTEand serumbiomarkersresults.Non-invasivetestmustbehoweverinterpretedcritically byspecialistsaccordingtoclinicalcontextandqualitycriteria.TEiscurrentlythe mostusedandvalidatedtechniquefordiagnosingcirrhosis(betteratrulingoutthan rulingin).Itsmainlimitationisitslimitedapplicabilityincaseofobesityandlackof operatorexperience.Monitoringofliverstiffnessduringantiviraltreatmenthas limitedvalue.InpatientswithHCVcirrhosisachievingSVR,follow-upwithTE isnotcurrentlyrecommendedbutdeservestobefurtherevaluated.
References
1.BravoAA,ShethSG,ChopraS.Liverbiopsy.NEnglJMed.2001;344(7):495–500.
2.CasteraL,PinzaniM.Non-invasiveassessmentofliver fibrosis:areweready?Lancet. 2010;375(9724):1419–20.
3.BedossaP,CarratF.Liverbiopsy:thebest,notthegoldstandard.JHepatol.2009;50(1):1–3.
4.EASL-ALEHClinicalPracticeGuidelines:non-invasivetestsforevaluationofliverdisease severityandprognosis.JHepatol.2015;63(1):237–64.
5.DietrichCF,BamberJ,BerzigottiA,BotaS,CantisaniV,CasteraL,etal.EFSUMB guidelinesandrecommendationsontheclinicaluseofliverultrasoundelastography,update 2017(LongVersion).UltraschallinderMedizin(Stuttgart,Germany:1980).2017;38(4): e16–47.
6.FerraioliG,FiliceC,CasteraL,ChoiBI,SporeaI,WilsonSR,etal.WFUMBguidelinesand recommendationsforclinicaluseofultrasoundelastography:Part3:liver.UltrasoundMed Biol.2015;41(5):1161–79.
7.KnodellRG,IshakKG,BlackWC,ChenTS,CraigR,KaplowitzN,etal.Formulationand applicationofanumericalscoringsystemforassessinghistologicalactivityinasymptomatic chronicactivehepatitis.Hepatology.1981;1(5):431–5.
8.IshakK,BaptistaA,BianchiL,CalleaF,DeGrooteJ,GudatF,etal.Histologicalgradingand stagingofchronichepatitis.JHepatol.1995;22(6):696–9.
9.BedossaP,PoynardT.AnalgorithmforthegradingofactivityinchronichepatitisC.The METAVIRcooperativestudygroup.Hepatology.1996;24:289–93.
10.BedossaP,MoucariR,ChelbiE,AsselahT,ParadisV,VidaudM,etal.Evidenceforaroleof nonalcoholicsteatohepatitisinhepatitisC:aprospectivestudy.Hepatology.2007;46 (2):380–7.
11.CasteraL,NegreI,SamiiK,BuffetC.Painexperiencedduringpercutaneousliverbiopsy. Hepatology.1999;30(6):1529–30.
12.CadranelJF,RufatP,DegosF.PracticesofliverbiopsyinFrance:resultsofaprospective nationwidesurvey.FortheGroupofEpidemiologyoftheFrenchAssociationfortheStudyof theLiver(AFEF).Hepatology.2000;32(3):477–81.
13.CasteraL,NegreI,SamiiK,BuffetC.Patient-administerednitrousoxide/oxygeninhalation providessafeandeffectiveanalgesiaforpercutaneousliverbiopsy:arandomizedplacebocontrolledtrial.AmJGastroenterol.2001;96(5):1553–7.
14.PiccininoF,SagnelliE,PasqualeG,GiustiG.Complicationsfollowingpercutaneousliver biopsy.Amulticentreretrospectivestudyon68,276biopsies.JHepatol.1986;2(2):165–73.
15.ColloredoG,GuidoM,SonzogniA,LeandroG.Impactofliverbiopsysizeonhistological evaluationofchronicviralhepatitis:thesmallerthesample,themilderthedisease.JHepatol. 2003;39(2):239–44.
16.MaharajB,MaharajRJ,LearyWP,CooppanRM,NaranAD,PirieD,etal.Sampling variabilityanditsinfluenceonthediagnosticyieldofpercutaneousneedlebiopsyofthe liver.Lancet.1986;1(8480):523–5.
17.RousseletMC,MichalakS,DupreF,CroueA,BedossaP,Saint-AndreJP,etal.Sourcesof variabilityinhistologicalscoringofchronicviralhepatitis.Hepatology.2005;41(2):257–64.
18.CasteraL,BedossaP.Howtoassessliver fibrosisinchronichepatitisC:serummarkersor transientelastographyvs.liverbiopsy?LiverInt:OfficialJournaloftheInternationalAssociationfortheStudyoftheLiver.2011;31(Suppl1):13–7.
19.CasteraL.NoninvasivemethodstoassessliverdiseaseinpatientswithhepatitisBor C.Gastroenterology.2012;142(6):1293–302.
20.Imbert-BismutF,RatziuV,PieroniL,CharlotteF,BenhamouY,PoynardT.Biochemical markersofliver fibrosisinpatientswithhepatitisCvirusinfection:aprospectivestudy. Lancet.2001;357(9262):1069–75.
21.FornsX,AmpurdanesS,LlovetJM,AponteJ,QuintoL,Martinez-BauerE,etal.IdentificationofchronichepatitisCpatientswithouthepatic fibrosisbyasimplepredictivemodel. Hepatology.2002;36(4Pt1):986–92.
22.WaiCT,GreensonJK,FontanaRJ,KalbfleischJD,MarreroJA,ConjeevaramHS,etal.A simplenoninvasiveindexcanpredictbothsignificant fibrosisandcirrhosisinpatientswith chronichepatitisC.Hepatology.2003;38(2):518–26.
23.PatelK,GordonSC,JacobsonI,HezodeC,OhE,SmithKM,etal.Evaluationofapanelof non-invasiveserummarkerstodifferentiatemildfrommoderate-to-advancedliver fibrosisin chronichepatitisCpatients.JHepatol.2004;41(6):935–42.
24.LeroyV,MonierF,BottariS,TrocmeC,SturmN,HilleretMN,etal.Circulatingmatrix metalloproteinases1,2,9andtheirinhibitorsTIMP-1andTIMP-2asserummarkersofliver fibrosisinpatientswithchronichepatitisC:comparisonwithPIIINPandhyaluronicacid.Am JGastroenterol.2004;99(2):271–9.
25.RosenbergWM,VoelkerM,ThielR,BeckaM,BurtA,SchuppanD,etal.Serummarkers detectthepresenceofliver fibrosis:acohortstudy.Gastroenterology.2004;127(6):1704–13.
26.SudA,HuiJM,FarrellGC,BandaraP,KenchJG,FungC,etal.Improvedpredictionof fibrosisinchronichepatitisCusingmeasuresofinsulinresistanceinaprobabilityindex. Hepatology.2004;39(5):1239–47.
27.AdamsLA,BulsaraM,RossiE,DeBoerB,SpeersD,GeorgeJ,etal.Hepascore:anaccurate validatedpredictorofliver fibrosisinchronichepatitisCinfection.ClinChem.2005;51 (10):1867–73.
28.CalesP,ObertiF,MichalakS,Hubert-FouchardI,RousseletMC,KonateA,etal.Anovel panelofbloodmarkerstoassessthedegreeofliver fibrosis.Hepatology.2005;42(6):1373–81.
29.LokAS,GhanyMG,GoodmanZD,WrightEC,EversonGT,SterlingRK,etal.Predicting cirrhosisinpatientswithhepatitisCbasedonstandardlaboratorytests:resultsoftheHALT-C cohort.Hepatology.2005;42(2):282–92.
30.IslamS,AntonssonL,WestinJ,LaggingM.CirrhosisinhepatitisCvirus-infectedpatientscan beexcludedusinganindexofstandardbiochemicalserummarkers.ScandJGastroenterol. 2005;40(7):867–72.
31.FontanaRJ,KleinerDE,BilonickR,TerraultN,AfdhalN,BelleSH,etal.Modelinghepatic fibrosisinAfricanAmericanandCaucasianAmericanpatientswithchronichepatitisCvirus infection.Hepatology.2006;44(4):925–35.
32.KodaM,MatunagaY,KawakamiM,KishimotoY,SuouT,MurawakiY.FibroIndex,a practicalindexforpredictingsignificant fibrosisinpatientswithchronichepatitis C.Hepatology.2007;45(2):297–306.
33.Vallet-PichardA,MalletV,NalpasB,VerkarreV,NalpasA,Dhalluin-VenierV,etal.FIB-4: aninexpensiveandaccuratemarkerof fibrosisinHCVinfection.comparisonwithliverbiopsy and fibrotest.Hepatology.2007;46(1):32–6.
34.FontanaRJ,GoodmanZD,DienstagJL,BonkovskyHL,NaishadhamD,SterlingRK,etal. Relationshipofserum fibrosismarkerswithliver fibrosisstageandcollagencontentinpatients withadvancedchronichepatitisC.Hepatology.2008;47(3):789–98.
35.SandrinL,FourquetB,HasquenophJM,YonS,FournierC,MalF,etal.Transient elastography:anewnoninvasivemethodforassessmentofhepatic fibrosis.UltrasoundMed Biol.2003;29(12):1705–13.
36.RoulotD,CzernichowS,LeClesiauH,CostesJL,VergnaudAC,BeaugrandM.Liver stiffnessvaluesinapparentlyhealthysubjects:influenceofgenderandmetabolicsyndrome. JHepatol.2008;48(4):606–13.
37.CasteraL,FornsX,AlbertiA.Non-invasiveevaluationofliver fibrosisusingtransient elastography.JHepatol.2008;48(5):835–47.
38.BoursierJ,ZarskiJP,deLedinghenV,RousseletMC,SturmN,LebailB,etal.Determination ofreliabilitycriteriaforliverstiffnessevaluationbytransientelastography.Hepatology. 2013;57(3):1182–91.
39.FraquelliM,RigamontiC,CasazzaG,ConteD,DonatoMF,RonchiG,etal.Reproducibility oftransientelastographyintheevaluationofliver fibrosisinpatientswithchronicliver disease.Gut.2007;56(7):968–73.
40.CasteraL,FoucherJ,BernardPH,CarvalhoF,AllaixD,MerroucheW,etal.Pitfallsofliver stiffnessmeasurement:a5-yearprospectivestudyof13,369examinations.Hepatology. 2010;51(3):828–35.
41.VuppalanchiR,SiddiquiMS,VanNattaML,HallinanE,BrandmanD,KowdleyK,etal. Performancecharacteristicsofvibration-controlledtransientelastographyforevaluationof nonalcoholicfattyliverdisease.Hepatology.2018;67(1):134–44.
42.MederackeI,WursthornK,KirschnerJ,RifaiK,MannsMP,WedemeyerH,etal.Foodintake increasesliverstiffnessinpatientswithchronicorresolvedhepatitisCvirusinfection.Liver Int:OfficialJournaloftheInternationalAssociationfortheStudyoftheLiver.2009;29 (10):1500–6.
43.BerzigottiA,DeGottardiA,VukoticR,SiramolpiwatS,AbraldesJG,Garcia-PaganJC,etal. Effectofmealingestiononliverstiffnessinpatientswithcirrhosisandportalhypertension. PLoSOne.2013;8(3):e58742.
44.Friedrich-RustM,PoynardT,CasteraL.Criticalcomparisonofelastographymethodsto assesschronicliverdisease.NatRevGastroenterolHepatol.2016;13(7):402–11.
45.KennedyP,WagnerM,CasteraL,HongCW,JohnsonCL,SirlinCB,etal.Quantitative elastographymethodsinliverdisease:currentevidenceandfuturedirections.Radiology. 2018;286(3):738–63.
46.EASLrecommendationsontreatmentofhepatitisC2015.JHepatol.2015;63(1):199–236.
47.AASLD/IDSA/IAS–USA.Recommendationsfortesting,managing,andtreatinghepatitis C. http://www.hcvguidelines.org [Internet].Accessed19Feb2015.
48.PoynardT,MorraR,HalfonP,CasteraL,RatziuV,ImbertBismutF,etal.Meta-analysesof Fibrotestdiagnosticvalueinchronicliverdisease.BMCGastroenterol.2007;7(1):40.
49.LinZH,XinYN,DongQJ,WangQ,JiangXJ,ZhanSH,etal.Performanceoftheaspartate aminotransferase-to-plateletratioindexforthestagingofhepatitisC-related fibrosis:an updatedmeta-analysis.Hepatology.2011;53(3):726–36.
50.DegosF,PerezP,RocheB,MahmoudiA,AsselineauJ,VoitotH,etal.Diagnosticaccuracyof FibroScanandcomparisontoliver fibrosisbiomarkersinchronicviralhepatitis:amulticenter prospectivestudy(theFIBROSTICstudy).JHepatol.2010;53(6):1013–21.
51.CasteraL,VergniolJ,FoucherJ,LeBailB,ChanteloupE,HaaserM,etal.Prospective comparisonoftransientelastography,Fibrotest,APRI,andliverbiopsyfortheassessmentof fibrosisinchronichepatitisC.Gastroenterology.2005;128(2):343–50.
52.ZiolM,Handra-LucaA,KettanehA,ChristidisC,MalF,KazemiF,etal.Noninvasive assessmentofliver fibrosisbymeasurementofstiffnessinpatientswithchronichepatitis C.Hepatology.2005;41(1):48–54.
53.AfdhalNH,BaconBR,PatelK,LawitzEJ,GordonSC,NelsonDR,etal.Accuracyof fibroscan,comparedwithhistology,inanalysisofliver fibrosisinpatientswithhepatitisBor C:aUnitedStatesmulticenterstudy.ClinGastroenterolHepatol:TheOfficialClinicalPractice JournaloftheAmericanGastroenterologicalAssociation.2015;13(4):772–9.
54.ArenaU,VizzuttiF,AbraldesJG,CortiG,StasiC,MoscarellaS,etal.Reliabilityoftransient elastographyforthediagnosisofadvanced fibrosisinchronichepatitisC.Gut.2008;57 (9):1288–93.
55.LupsorM,BadeaR,StefanescuH,GrigorescuM,SparchezZ,SerbanA,etal.Analysisof histopathologicalchangesthatinfluenceliverstiffnessinchronichepatitisC.Resultsfroma cohortof324patients.JGastrointestinLiverDis.2008;17(2):155–63.
56.ZarskiJP,SturmN,GuechotJ,ParisA,ZafraniES,AsselahT,etal.Comparisonofnineblood testsandtransientelastographyforliver fibrosisinchronichepatitisC:TheANRSHCEP-23 study.JHepatol.2012;56:55–62.
57.ChonYE,ChoiEH,SongKJ,ParkJY,KimdoY,HanKH,etal.Performanceoftransient elastographyforthestagingofliver fibrosisinpatientswithchronichepatitisB:ametaanalysis.PLoSOne.2012;7(9):e44930.
58.Friedrich-RustM,OngMF,MartensS,SarrazinC,BojungaJ,ZeuzemS,etal.Performanceof transientelastographyforthestagingofliver fibrosis:ameta-analysis.Gastroenterology. 2008;134(4):960–74.
59.StebbingJ,FaroukL,PanosG,AndersonM,JiaoLR,MandaliaS,etal.Ameta-analysisof transientelastographyforthedetectionofhepatic fibrosis.JClinGastroenterol.2010;44 (3):214–9.
60.TalwalkarJA,KurtzDM,SchoenleberSJ,WestCP,MontoriVM.Ultrasound-basedtransient elastographyforthedetectionofhepatic fibrosis:systematicreviewandmeta-analysis.Clin GastroenterolHepatol:TheOfficialClinicalPracticeJournaloftheAmericanGastroenterologicalAssociation.2007;5(10):1214–20.
61.TsochatzisEA,GurusamyKS,NtaoulaS,CholongitasE,DavidsonBR,Burroughs AK.Elastographyforthediagnosisofseverityof fibrosisinchronicliverdisease:ametaanalysisofdiagnosticaccuracy.JHepatol.2011;54(4):650–9.
62.ShaheenAA,WanAF,MyersRP.FibroTestandFibroScanforthepredictionofhepatitis C-related fibrosis:asystematicreviewofdiagnostictestaccuracy.AmJGastroenterol. 2007;102(11):2589–600.
63.Friedrich-RustM,NierhoffJ,LupsorM,SporeaI,Fierbinteanu-BraticeviciC,StrobelD,etal. Performanceofacousticradiationforceimpulseimagingforthestagingofliver fibrosis:a pooledmeta-analysis.JViralHepat.2012;19(2):e212–9.
64.NierhoffJ,ChavezOrtizAA,HerrmannE,ZeuzemS,Friedrich-RustM.Theefficiencyof acousticradiationforceimpulseimagingforthestagingofliver fibrosis:ameta-analysis.Eur Radiol.2013;23(11):3040–53.
65.HuX,QiuL,LiuD,QianL.AcousticRadiationForceImpulse(ARFI)Elastographyfor noninvasiveevaluationofhepatic fibrosisinchronichepatitisBandCpatients:asystematic reviewandmeta-analysis.MedUltrason.2017;19(1):23–31.
66.BotaS,HerknerH,SporeaI,SalzlP,SirliR,NeghinaAM,etal.Meta-analysis:ARFI elastographyversustransientelastographyfortheevaluationofliver fibrosis.LiverInt: OfficialJournaloftheInternationalAssociationfortheStudyoftheLiver.2013;33 (8):1138–47.
67.FerraioliG,TinelliC,DalBelloB,ZicchettiM,FiliceG,FiliceC.Accuracyofreal-timeshear waveelastographyforassessingliver fibrosisinchronichepatitisC:apilotstudy.Hepatology. 2012;56(6):2125–33.
68.LeungVY,ShenJ,WongVW,AbrigoJ,WongGL,ChimAM,etal.Quantitative elastographyofliver fibrosisandspleenstiffnessinchronichepatitisBcarriers:comparison ofshear-waveelastographyandtransientelastographywithliverbiopsycorrelation.Radiology.2013;269(3):910–8.
69.HerrmannE,deLédinghenV,CassinottoC,ChuWCW,LeungVYF,FerraioliG,etal. Assessmentofbiopsy-provenliver fibrosisbytwo-dimensionalshearwaveelastography:an individualpatientdata-basedmeta-analysis.Hepatology.2018;67(1):260–72.
70.CassinottoC,LapuyadeB,MouriesA,HiriartJB,VergniolJ,GayeD,etal.Non-invasive assessmentofliver fibrosiswithimpulseelastography:comparisonofSupersonicShear ImagingwithARFIandFibroScan(R).JHepatol.2014;61(3):550–7.
71.GerberL,KasperD,FittingD,KnopV,VermehrenA,SprinzlK,etal.Assessmentofliver fibrosiswith2-Dshearwaveelastographyincomparisontotransientelastographyand acousticradiationforceimpulseimaginginpatientswithchronicliverdisease.Ultrasound MedBiol.2015;41(9):2350–9.
72.SinghS,VenkateshSK,WangZ,MillerFH,MotosugiU,LowRN,etal.Diagnostic performanceofmagneticresonanceelastographyinstagingliver fibrosis:asystematicreview andmeta-analysisofindividualparticipantdata.ClinicalGastroenterolHepatol:Theofficial ClinicalPracticeJournaloftheAmericanGastroenterologicalAssociation.2015;13 (3):440–51.
73.WangQB,ZhuH,LiuHL,ZhangB.Performanceofmagneticresonanceelastographyand diffusion-weightedimagingforthestagingofhepatic fibrosis:ameta-analysis.Hepatology. 2012;56(1):239–47.
74.BohteAE,deNietA,JansenL,BipatS,NederveenAJ,VerheijJ,etal.Non-invasive evaluationofliver fibrosis:acomparisonofultrasound-basedtransientelastographyandMR elastographyinpatientswithviralhepatitisBandC.EurRadiol.2014;24(3):638–48.
75.HuwartL,SempouxC,VicautE,SalamehN,AnnetL,DanseE,etal.Magneticresonance elastographyforthenoninvasivestagingofliver fibrosis.Gastroenterology.2008;135 (1):32–40.
76.IchikawaS,MotosugiU,MorisakaH,SanoK,IchikawaT,TatsumiA,etal.Comparisonof thediagnosticaccuraciesofmagneticresonanceelastographyandtransientelastographyfor hepatic fibrosis.MagnResonImaging.2015;33(1):26–30.
77.CalesP,BoursierJ,LebigotJ,deLedinghenV,AubeC,HubertI,etal.Liver fibrosis diagnosisbybloodtestandelastographyinchronichepatitisC:agreementorcombination? AlimentPharmacolTher.2017;45(7):991–1003.
78.DucancelleA,LeroyV,VergniolJ,SturmN,LeBailB,ZarskiJP,etal.Asingletest combiningbloodmarkersandelastographyismoreaccuratethanother fibrosistestsinthe maincausesofchronicliverdiseases.JClinGastroenterol.2017;51(7):639–49.
79.HezodeC,CasteraL,Roudot-ThoravalF,Bouvier-AliasM,RosaI,RoulotD,etal.Liver stiffnessdiminisheswithantiviralresponseinchronichepatitisC.AlimentPharmacolTher. 2011;34(6):656–63.
80.NascimbeniF,LebrayP,FedchukL,OliveiraCP,Alvares-da-SilvaMR,VaraultA,etal. Significantvariationsinelastometrymeasurementsmadewithinshort-terminpatientswith chronicliverdiseases.ClinGastroenterolHepatol:TheOfficialClinicalPracticeJournalofthe AmericanGastroenterologicalAssociation.2015;13(4):763–71.
81.PoynardT,Imbert-BismutF,RatziuV,ChevretS,JardelC,MoussalliJ,etal.Biochemical markersofliver fibrosisinpatientsinfectedbyhepatitisCvirus:longitudinalvalidationina randomizedtrial.JViralHepat.2002;9(2):128–33.
82.PoynardT,McHutchisonJ,MannsM,MyersRP,AlbrechtJ.Biochemicalsurrogatemarkers ofliver fibrosisandactivityinarandomizedtrialofpeginterferonalfa-2bandribavirin. Hepatology.2003;38(2):481–92.
83.FontanaRJ,BonkovskyHL,NaishadhamD,DienstagJL,SterlingRK,LokAS,etal.Serum fibrosismarkerlevelsdecreaseaftersuccessfulantiviraltreatmentinchronichepatitisC patientswithadvanced fibrosis.ClinicalGastroenterolHepatol:TheOfficialClinicalPractice JournaloftheAmericanGastroenterologicalAssociation.2009;7(2):219–26.
84.OgawaE,FurusyoN,ToyodaK,TakeokaH,MaedaS,HayashiJ.ThelongitudinalquantitativeassessmentbytransientelastographyofchronichepatitisCpatientstreatedwithpegylated interferonalpha-2bandribavirin.AntivirRes.2009;83(2):127–34.
85.VergniolJ,FoucherJ,CasteraL,BernardPH,TournanR,TerrebonneE,etal.Changesof non-invasivemarkersandFibroScanvaluesduringHCVtreatment.JViralHepat.2009;16 (2):132–40.
86.MartinezSM,Fernandez-VaroG,GonzalezP,SampsonE,BrugueraM,NavasaM,etal. Assessmentofliver fibrosisbeforeandafterantiviraltherapybydifferentserummarkerpanels inpatientswithchronichepatitisC.AlimenPharmacolTher.2011;33(1):138–48.
87.PoynardT,MoussalliJ,MunteanuM,ThabutD,LebrayP,RudlerM,etal.Slowregressionof liver fibrosispresumedbyrepeatedbiomarkersaftervirologicalcureinpatientswithchronic hepatitisC.JHepatol.2013;59(4):675–83.
88.StasiC,ArenaU,ZignegoAL,CortiG,MontiM,TriboliE,etal.Longitudinalassessmentof liverstiffnessinpatientsundergoingantiviraltreatmentforhepatitisC.DigLiverDis.2013;45 (10):840–3.
89.VergniolJ,BoursierJ,CoutzacC,BertraisS,FoucherJ,AngelC,etal.Evolutionof noninvasivetestsofliver fibrosisisassociatedwithprognosisinpatientswithchronichepatitis C.Hepatology.2014;60(1):65–76.
90.BachofnerJA,ValliPV,KrogerA,BergaminI,KunzlerP,BasergaA,etal.Directantiviral agenttreatmentofchronichepatitisCresultsinrapidregressionoftransientelastographyand fibrosismarkers fibrosis-4scoreandaspartateaminotransferase-plateletratioindex.LiverInt: OfficialJournaloftheInternationalAssociationfortheStudyoftheLiver.2017;37(3):369–76.
91.MandorferM,KozbialK,FreissmuthC,SchwablP,StattermayerAF,ReibergerT,etal. Interferon-freeregimensforchronichepatitisCovercometheeffectsofportalhypertensionon virologicalresponses.AlimentPharmacolTher.2015;42(6):707–18.
92.PoynardT,McHutchisonJ,MannsM,TrepoC,LindsayK,GoodmanZ,etal.Impactof pegylatedinterferonalfa-2bandribavirinonliver fibrosisinpatientswithchronichepatitis C.Gastroenterology.2002;122(5):1303–13.
93.ShiratoriY,ImazekiF,MoriyamaM,YanoM,ArakawaY,YokosukaO,etal.Histologic improvementof fibrosisinpatientswithhepatitisCwhohavesustainedresponsetointerferon therapy.AnnInternMed.2000;132(7):517–24.
94.SinghS,FacciorussoA,LoombaR,Falck-YtterYT.Magnitudeandkineticsofdecreasein liverstiffnessafterantiviraltherapyinpatientswithchronichepatitisC:asystematicreview andmeta-analysis.ClinGastroenterolHepatol:TheOfficialClinicalPracticeJournalofthe AmericanGastroenterologicalAssociation.2018;16(1):27–38.
95.vanderMeerAJ,FeldJJ,HoferH,AlmasioPL,CalvarusoV,Fernandez-RodriguezCM,etal. Riskofcirrhosis-relatedcomplicationsinpatientswithadvanced fibrosisfollowinghepatitisC viruseradication.JHepatol.2017;66(3):485–93.
96.DiMarcoV,CalvarusoV,FerraroD,BavettaMG,CabibboG,ConteE,etal.Effectsof eradicatinghepatitisCvirusinfectioninpatientswithcirrhosisdifferwithstageofportal hypertension.Gastroenterology.2016;151(1):130–9.
97.D’AmbrosioR,AghemoA,FraquelliM,RumiMG,DonatoMF,ParadisV,etal.The diagnosticaccuracyofFibroscanforcirrhosisisinfluencedbylivermorphometryinHCV patientswithasustainedvirologicalresponse.JHepatol.2013;59(2):251–6.
98.D’AmbrosioR,DegasperiE,AghemoA,FraquelliM,LamperticoP,RumiMG,etal. Serologicaltestsdonotpredictresidual fibrosisinhepatitisCcirrhoticswithasustained virologicalresponsetointerferon.PLoSOne.2016;11(6):e0155967.
99.YouMW,KimKW,PyoJ,HuhJ,KimHJ,LeeSJ,etal.AMeta-analysisforthediagnostic performanceoftransientelastographyforclinicallysignificantportalhypertension.Ultrasound MedBiol.2017;43(1):59–68.
100.BerzigottiA.Non-invasiveevaluationofportalhypertensionusingultrasoundelastography.J Hepatol.2017;67(2):399–411.
101.CasteraL,PinzaniM,BoschJ.Noninvasiveevaluationofportalhypertensionusingtransient elastography.JHepatol.2012;56(3):696–703.
102.ShiKQ,FanYC,PanZZ,LinXF,LiuWY,ChenYP,etal.Transientelastography:ametaanalysisofdiagnosticaccuracyinevaluationofportalhypertensioninchronicliverdisease. LiverInt:OfficialJournaloftheInternationalAssociationfortheStudyoftheLiver.2013;33 (1):62–71.
103.KimBK,HanKH,ParkJY,AhnSH,KimJK,PaikYH,etal.Aliverstiffnessmeasurementbased,noninvasivepredictionmodelforhigh-riskesophagealvaricesinB-virallivercirrhosis. AmJGastroenterol.2010;105(6):1382–90.
104.BerzigottiA,SeijoS,ArenaU,AbraldesJG,VizzuttiF,Garcia-PaganJC,etal.Elastography, spleensize,andplateletcountidentifyportalhypertensioninpatientswithcompensated cirrhosis.Gastroenterology.2013;144(1):102–11.
105.deFranchisR,BavenoVIF.Expandingconsensusinportalhypertension:reportoftheBaveno VIConsensusWorkshop:stratifyingriskandindividualizingcareforportalhypertension.J Hepatol.2015;63(3):743–52.
106.AbraldesJG,BureauC,StefanescuH,AugustinS,NeyM,BlascoH,etal.Noninvasivetools andriskofclinicallysignificantportalhypertensionandvaricesincompensatedcirrhosis:the “Anticipate” study.Hepatology.2016;64(6):2173–84.
107.JangoukP,TurcoL,DeOliveiraA,SchepisF,VillaE,Garcia-TsaoG.Validating, deconstructingandrefiningBavenocriteriaforrulingouthigh-riskvaricesinpatientswith compensatedcirrhosis.LiverInt:OfficialJournaloftheInternationalAssociationfortheStudy oftheLiver.2017;37(8):1177–83.
108.MauriceJB,BrodkinE,ArnoldF,NavaratnamA,PaineH,KhawarS,etal.Validationofthe BavenoVIcriteriatoidentifylowriskcirrhoticpatientsnotrequiringendoscopicsurveillance forvarices.JHepatol.2016;65(5):899–905.
109.StafylidouM,PaschosP,KatsoulaA,MalandrisK,IoakimK,BekiariE,etal.Performanceof BavenoVIandexpandedBavenoVIcriteriaforexcludinghigh-riskvaricesinpatientswith chronicliverdiseases:asystematicreviewandmeta-analysis.ClinGastroenterolHepatol:The
OfficialClinicalPracticeJournaloftheAmericanGastroenterologicalAssociation.2019;17 (9):1744–55.
110.SzakacsZ,ErossB,SoosA,MatraiP,SzaboI,PetervariE,etal.Bavenocriteriasafely identifypatientswithcompensatedadvancedchronicliverdiseasewhocanavoidvariceal screeningendoscopy:adiagnostictestaccuracymeta-analysis.FrontPhysiol.2019;10:1028.
111.PoynardT,VergniolJ,NgoY,FoucherJ,MunteanuM,MerroucheW,etal.Stagingchronic hepatitisCinsevencategoriesusing fibrosisbiomarker(FibroTest)andtransientelastography (FibroScan(R)).JHepatol.2014;60(4):706–14.
112.VergniolJ,FoucherJ,TerrebonneE,BernardPH,leBailB,MerroucheW,etal.Noninvasive testsfor fibrosisandliverstiffnesspredict5-yearoutcomesofpatientswithchronichepatitis C.Gastroenterology.2011;140(7):1970–9.
113.PonsM,Rodriguez-TajesS,EstebanJI,MarinoZ,VargasV,LensS,etal.Non-invasive predictionofliver-relatedeventsinpatientswithHCV-associatedcompensatedadvanced chronicliverdiseaseafteroralantivirals.JHepatol.2020;72(3):472–80.
114.AsraniSK,TalwalkarJA,KamathPS,ShahVH,SaracinoG,JenningsL,etal.Roleof magneticresonanceelastographyincompensatedanddecompensatedliverdisease.JHepatol. 2014;60(5):934–9.
115.CassinottoC,CharrieA,MouriesA,LapuyadeB,HiriartJB,VergniolJ,etal.Liverand spleenelastographyusingsupersonicshearimagingforthenon-invasivediagnosisofcirrhosis severityandoesophagealvarices.DigLiverDis.2015;47(8):695–701.
116.VermehrenJ,PoltaA,ZimmermannO,HerrmannE,PoynardT,HofmannWP,etal. Comparisonofacousticradiationforceimpulseimagingwithtransientelastographyforthe detectionofcomplicationsinpatientswithcirrhosis.LiverInt:OfficialJournaloftheInternationalAssociationfortheStudyoftheLiver.2012;32(5):852–8.
