Spleen Stiffness Probability Index (SSPI): A simple and accurate method to detect esophageal varices in patients with compensated liver cirrhosis

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ContentslistsavailableatScienceDirect

Annals

of

Hepatology

j o ur na l h o me p a g 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

Original

article

Spleen

Stiffness

Probability

Index

(SSPI):

A

simple

and

accurate

method

to

detect

esophageal

varices

in

patients

with

compensated

liver

cirrhosis

Mauro

Giuffrè

a,∗

_,

_Daniele

_Macor

a

_,

_Flora

_Masutti

b

_,

_Cristiana

_Abazia

b

_,

_Fabio

_Tinè

b

_,

Giorgio

Bedogni

c

_,

_Claudio

_Tiribelli

c

_,

_Lory

_Saveria

_Crocè

a,b,c

a_Dipartimento_{Universitario}_Clinico_Di_Scienze_Mediche_Chirurgiche_e_Della_Salute,_Università_Degli_Studi_Di_Trieste,_Italy

b_Clinica_Patologie_Fegato,_Azienda_Sanitaria_{Universitaria}_Integrata_Di_Trieste,_Italy

c_Fondazione_Italiana_Fegato,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received10June2019

Accepted12September2019

Availableonline23October2019

Keywords: Spleenelastography Spleenstiffness Liverstiffness Esophagealvarices Liverelastography

a

b

s

t

r

a

c

t

Intruductionandobjectives:Recentﬁndingspointedoutthatevenlow-riskesophagealvarices(EVs)are markersofsevereprognosis.Accordingly,weanalyzedspleenstiffness(SS)asanon-invasivemethodto predictEVsofanygradeinacohortofpatientswithcompensatedlivercirrhosis.

Method:WemeasuredSSandliverstiffness(LS)usingpoint-Shear-WaveElastography(pSWE)with PhilipsAfﬁniti70systemin210cirrhoticpatientswhohadundergoneendoscopicscreeningforEVs.We comparedSSandLSpredictivecapabilityforEVsofanygrade.

Results:SSwashigherincirrhoticpatientswithEVsifcomparedtopatientswithoutEVs(p<0.001).The cut-offanalysisdetected31kPa(100%sensitivityandnegativepredictivevalue)asthevaluetorule-out EVsand69kPa(100%speciﬁcityandpositivepredictivevalue)torule-inEVs.Besides,wedeveloped theSpleenStiffnessProbabilityIndex(SSPI),thatcanprovideaprobabilityofpresence/absenceofEVs. SSPIwasthebestmodelaccordingtoalldiscriminativeandcalibrationmetrics(AIC=120,BIC=127, AUROC=0.95,Pseudo-R2=0.74).SSdemonstratedhighercorrelationwithspleenbipolardiameterand spleensurface(r=0.52/0.55)ifcomparedtoLS(r=0.30/0.25)–andwithplateletcountaswell(r=0.67 vsr=0.4).

Conclusion:SSshowedsigniﬁcantlyhigherperformancethanotherparameters,provingtobethebest non-invasivetestinthescreeningofEVs:bydirectlyapplyingSScut-offof31kPa,ourdepartmentcould havesafelyavoidedendoscopyin36%ofpatients.Despitecut-offanalyses,itwaspossibletocreatea probabilitymodelthatcouldfurtherstratifylow-riskfromhigh-riskpatients(foranygradeofEVs).

1. Introduction

Portalhypertension(PH)isacommoncomplicationofliver

cir-rhosis. Theincrease in portal pressurebeyondthethreshold of

10mmHg(clinicallysigniﬁcantportalhypertension,CSPH)deﬁnes

amilestoneinthenaturalhistoryoflivercirrhosis,increasingthe

riskofesophagealvarices(EVs)andmanifestationof

decompen-satingevents(suchasascites,varicealhemorrhage,andhepatic

encephalopathy)thatmarkthetransitiontoa stageofliver

dis-easecharacterizedbyasigniﬁcantlyreducedlifeexpectancy[1,2].

∗ Correspondingauthorat:UniversitàdegliStudidiTrieste,Dipartimento

Univer-sitarioClinicodiScienzeMedicheChirurgicheedellaSalute–StradadiFiume,447

Trieste,Italy.

E-mailaddress:[email protected](M.Giuffrè).

Historically,EVswerediagnosed innearly50% ofpatientswith

cirrhosis.Nowadays,theadventofdirectantiviralagents(DAA),

whichallowedsuccessfuleradicationofhepatitisC virus(HCV),

togetherwiththehighsensitivityofliverelastographyinclassifying

liverﬁbrosis,hasdrasticallychangedtheepidemiologicalscenario.

However,EVsdevelopmentdependsontheseverityofliverdisease

[3]andthedegreeofportalpressure[4,5],thereforeappropriate

risk-stratiﬁcationisassessedbythetwoinvasivegold-standards

–hepatic veinpressure gradient(HVPG)measurements[6]and

esophagogastroduodenoscopy(EGD)–whichallowproper

medi-cal/endoscopicproceduresinpatientswithhigh-riskEVs(HRVs),

thus reducing the risk of hemorrhages. However, the invasive

natureofbothEGDandHVPGleadstosigniﬁcantpatientdiscomfort

andincreasedhealthcarecosts.Asaresult,thereisagreat

inter-estindevelopingnon-invasivetechniques(NITs)withacceptable

https://doi.org/10.1016/j.aohep.2019.09.004

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diagnosticaccuracytopredicttheoccurrenceandsizeofEVs,thus

avoidinginvasivemethodsinlow-riskpatients.Theappropriate

prescriptionofscreeningendoscopyincirrhoticpatientshasbeen

amatterofdiscussioninthelastthreedecades[7].Several

sero-logicalandradiologicalparametershavebeenproposedtopredict

EVssuchasliverstiffness(LS),plateletcounttospleendiameter

ratio(PSR)[8],andliverstiffness-spleensizetoplateletratiorisk

score(LSPS)[9].In2015,theBavenoVI consensusafﬁrmedthe

importanceofNITsinthescreeningofEVs,withparticular

empha-sisonLS,concludingthatindividualswithLS<20kPaandplatelet

count>150g/LwereconsideredunlikelytohaveHRVs(<5%)[10].

Todate,severalstudiesvalidatedthesecriteria,conﬁrmingthat

followingBavenoVIcut-offscouldaccuratelyclassify98–100%of

patientswhocansafelyavoidendoscopy[11,12].Asigniﬁcant

limi-tationofthesecriteriacorrespondstotheconsiderablylownumber

of spared EGD (15–25%) [13,14], which has beenimproved by

selectingdifferentLSandplateletcountthresholds[14–16].Since

2010,spleenstiffness(SS)hasbeenstudiedasamoreperformant

predictorofPH[17],anditwasrecentlycombinedwithBaveno

VIcriteria,allowingtospareEGDin44%ofpatientswitharateof

missedHRVs<5%[18].

Mostofthestudieswhichinvestigatedliverandspleenstiffness

focusedonitsdiscriminatoryrole inHRVsand performed

stiff-nessmeasurements usingtransientelastography (TE)machines

inpatients withongoing liverinjuringfactors. Thatbeingsaid,

accordingtobothEuropeanandAmericanguidelines,EGDisstill

recommendedinthefollow-upofcompensatedcirrhoticpatients

withadifferenttimeinterval(fromonetothreeyears)accordingto

(i)previousdetectionofEVsand(ii)ongoing/quiescentliverinjury

[10,19].ThecontinuousrelyonEGDcreatesanever-endingcycle

ofinvasivediagnosticroutineduringthelifetimeofthecirrhotic

patient.

Thepresentstudyaimedatevaluatingthepredictivecapability

ofSSonEVs(ofanygrade),bythedevelopmentofaprobability

modelinpatientswithcompensatedcirrhosisandwithout

ongo-ingfactorspromotingliverinjury(i.e.,alcoholabuse,activeHCV

infection,etc).Besides,wewantedtocompareSStootherNITs.We

alreadyassessedthereproducibilityelsewhere[20–24].

2. Patientsandmethods

2.1. Studydesign

Inthiscross-sectionalstudy,weenrolledconsecutivepatients

withadiagnosisoflivercirrhosisreferredtotheDepartmentof

Health,Medical, and Surgical Sciences of theUniversity of

Tri-este(Italy)andevaluatedattheLiverClinicbetweenJanuary2016

andDecember2018.Fromanoriginalcohortof650individuals

withlivercirrhosis,only220(Fig.1)patientswithcompensated

advancedchronicliverdisease(cACLD)mettheenrollment

crite-ria.Bothliverandspleenelastographymeasureswerereliablein

210patients,84ofwhom(40%)hadEVs.Wehadpreviously

mea-suredSSinacontrolgroupof100healthyindividuals,wherewe

alsoassessedSSinter-operatoragreement[21,22].

2.2. Inclusioncriteria

Weselectedadultpatientswithlivercirrhosis,whosediagnosis

wasconﬁrmedbyimaging,elastographyand/orhistological

eval-uationandbloodtests.Asperthestandarddiagnosticprocedure,

thepatientsunderwentanEGDwithanevaluationof the

pres-ence/absenceofesophagealand/orgastricvaricesandcongestive

gastropathy.Patientsalsounderwentanelastographicexamination

oftheliverandspleenwithamaximumintervalof6monthsfrom

theendoscopy.Onlypatientswithliverstiffness>11.34kPa[25],a

valuecompatiblewithsevereﬁbrosis(F4accordingtoMETAVIR),

wereincluded.

2.3. Exclusioncriteria

Patientswithnoinformedconsentwerecategoricallyexcluded.

Wealsoexcludedpregnantwomen,patientswithcurrentalcohol

abuse,patientswithongoingHCVinfection(orSVR<12months),

patientswithpresenceofdecompensatingevents(suchashepatic

encephalopathy,variceal hemorrhage, ascites, and spontaneous

bacterialperitonitis), previousendoscopicEVs bandingligation,

ongoingintakeofnon-selectivebeta-blockers(NSBB),historyof

portal vein thrombosis, placement of transjugular intrahepatic

portosystemicshunt(TIPS),non-cirrhoticcausesofPH,and

cur-rent/recentdiagnosisofhepatocellularcarcinoma[26].

2.4. Ultrasonographicandelastographicexamination

Acompleteevaluationoftheliverandsplenic-portalaxiswas

performedusingaPhilipsAfﬁniti70ultrasonographysystemwith

a 1–5MHzconvex probe. The samplingof theportal ﬂow was

performedatthehepatichilumlevelwithaprobepositionedin

theintercostalwindow,andwiththeacquisitionofatleastthree

values.Theportalcaliberwasevaluatedatthelevelbetweenthe

portalveinandthehepaticarterywiththeprobepositionedatthe

epigastric-sub-focallevel.Theportalveindiameterwasexpressed

incm,whiletheportalveinﬂowvelocitywasexpressedincm/s.

Thespleenwasevaluatedinthesupinepositionpatientviathe

intercostalwindowandtryingtoacquirethebroadestpossiblescan

thatincludedthesplenichilum.Boththebipolarspleendiameter

(expressedincm)andthesplenicarea(expressedincm2₎_were

measuredattheorganhilum.

2.5. Elastographicexamination

Inordertoavoidconfoundingfactorsinstiffnessmeasurement,

thepatientshadtoarrivewhilefastingforatleast3handwithno

caffeineintakeduringtheprevioushour[27,28].

Liverandspleenelastographywereperformedwiththesame

instrumentusedforultrasonography,operatingtheElastPQ

evalua-tionprotocol.Themachineconvertedthemeasurefromm/stokPa,

withtheformula:E=cs2–whereEistheYoungModulus(kPa),

isthedensityofthetissue(kg/m3_),_and_c

sistheshearwavespeed

(m/s).Allmeasureswereacquiredbyanexperiencedoperatorwith

fouryearsofexperienceinultrasoundandelastography.

Patientswerepositionedinsupinedecubituswiththerightarm

(liver)orleftarm(spleen)inmaximalabductioninordertoincrease

theintercostalacousticwindow.Theregionofinterest(ROI)was

placedbetweentheVIIandVIIIsegmentsatleast1.5cmfromthe

hepaticcapsule(LS)andatthesplenichilumorlowerpoleatleast

1cmfromthespleniccapsule(SS).TheROIwasaccuratelylocated

inanareawithoutlargelivervessels,bileducts,andribshadows.

Duringtheacquisition,thepatientwasrequestedtoholdhis/her

breathfor5s.Allmeasuresobtainedafteradeepinspiration;

max-imalexpirationsandValsalvamaneuverwerediscarded[29,30].In

10%ofcases,breath-holdwaspracticedwiththepatientpriorto

initiatingelastography.

Tendifferentvalidelastographicmeasurementswereobtained

inallsubjectsbothintheliverandinthespleen,andthemedian

valuewasused.The measureobtainedwasacquired onlyifits

standarddeviationwas<30%.AccordingtoBoursieretal.stiffness

measurementswereconsideredpoorlyreliablewhentheyshowed

aninterquartile(IQR)/median(M)ratio≥0.35;reliablewhenthey

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n = 650 PATIENTS WITH LIVER CIRRHOSIS

n = 210 PATIENTS WITH RELIABLE LIVER AND

SPLEEN STIFFNESS MEASUREMENTS

Individuals with reliable liver and spleen stiffness measurements Ongoing liver injury? (i.e. active HV infection, alcohol abuse, etc) Decompensated cirrhosis?

(i.e. ascites, variceal hemorrhage, hepatic encephalopathy, etc)

Current use of non-selective beta-blockers or previous esophageal band ligation? NO n = 500 NO n = 363 NO n = 220 YES n = 150 YES n = 137 YES n = 143

Fig.1.Fromtheoriginalcohortof650patientsdiagnosedwithlivercirrhosis,150hadongoingliverinjury.Fromtheremaining500,weselectedtheones(363)without

previoushistoryofdecompensatingevents.Then,wechosepatientswithouttherapeuticconfoundingfactors(suchascurrentuseofnon-selectivebeta-blockersandprevious

esophagealbandligation),thatcouldalterspleenstiffnessvalues.Fromthisgroupof220patients,210hadreliableliverandspleenstiffnessmeasurements.

Wedeﬁned“technicalfailure”theimpossibilitytoobtainanyvalue

oranIQR/M≥0.35andselectedvalueswithanIQR/M<0.30.

2.6. Esophagogastroduodenoscopy

All patientsunderwent a complete endoscopic examination

conducteduptothesecondduodenalportion.Theesophaguswas

evaluatedinsearchofesophagealvarices,which,ifpresent,were

classiﬁedwiththeBeppuclassiﬁcation(1981)[32].Indetail,the

localization(L),theshape,andsize(F),thecolor(C),thepresence

orabsenceofredcolorsigns(RS),andthepresenceorabsenceof

esophagitis(E)wereevaluated.Thegastricchamber,also

evalu-atedinretroversionwithadequatevisualizationofthefundusand

cardiacregion,wasinspectedforsignsofcongestivegastropathy

and/orgastricvarices.

2.7. Clinicalevaluationofthepatientandlaboratorytests

Eachpatientunderwentblood testsanda completephysical

examinationatthetimeofthevisit.Weevaluated:weight,height,

bodymassindex(BMI),etiologyofcirrhosis,clinicalsignsofliver

diseasedecompensation (presence/absence ofascites, and

hep-aticencephalopathy).Subsequently,thefollowingbloodlaboratory

valueswerecollected:AST,ALT,GGT, creatinine,total bilirubin,

albumin,INR,andplateletcount.Thefollowingscoreswerethen

calculated:ModelforEnd-stageLiverDisease(MELD),Child–Pugh

(CP),ASTtoPlateletRatioIndex(APRI),PSR,LSPS.

2.8. Statisticalanalysis

MostcontinuousvariableswerenotGaussian-distributed,and

allarereportedasmedian(50thpercentile)andinterquartilerange

(IQR,25thand75thpercentiles).Discretevariablesarereportedas

thenumberandproportionofsubjectswiththecharacteristicof

interest.

Between-group comparisons of discrete variables were

per-formed using Pearson’s Chi-square test and those of

contin-uous variables using median regression [33]. The association

betweenvarices(discrete;0=no,1=yes)andthefourcontinuous

predictors of interest (liver stiffness, spleen stiffness, spleen

diameterandplatelets)wasevaluatedusingunivariablelogistic

regression[34].

Weusedunivariablefractionalpolynomialstotestwhetherthe

logits of thepredictors werelinear and transformedboth liver

stiffnessandspleenstiffnessusinganinversesquareroot

transfor-mationtomaketheirlogitslinear[35].Toevaluatethecollinearity

ofSS,LS,spleensize,andplateletcount,correlationswereassessed

usingtheSpearmanrank-ordercorrelationcoefﬁcient[36].

WecomparedmodelsusingAkaikeinformationcriterion(AIC)

and the Bayesian information criterion (BIC) and calculated

Nagelkerkepseudo-R2_and_the_area_under_the_{receiver-operating}

characteristiccurve(AUROC).Thediagnosticaccuracywas

calcu-latedusingsensitivity,speciﬁcity,positivepredictivevalue(PPV),

negativepredictivevalue(NPV),accuracy,positivelikelihoodratio

(+LR),andnegativelikelihoodratio(−LR).Optimalcut-offvalues

werechosen tosafely rule-outpatientswithEVsand HRVsfor

screening purposes. Accordingly, we selectedSS and LS cut-off

thresholdwithmaximalsensitivityandNPVandaminimal−LR.

3. Results

Onehundredandthirty(62%)outof210patientsweremale.

Thepredominant etiologiesof theliverdiseasewererelated to

viralinfection(n=79,36%)andalcoholabuse (n=74,35%).One

hundredandseventy-ninepatientswereCP-A(85%),31wereCP-B

(15%),andthemedian(IQR)MELDvaluewas8(7–10).Themedian

(IQR)LSmedianwas18.3kPa(13.50–24.70),themedian(IQR)SS

was34.9kPa (28–46.3). The median (IQR)APRI score was0.70

(0.43–1.18),themedian(IQR)PSRscorewas904.5(658.65–1337),

andLSPSscorewas2.18(1.20–3.57).Thepatientsincludedinthe

study were divided into two sub-groups: with (n=84, 40%)or

without(n=126,60%)EVs.BetweenpatientswithEVs,72(85.7%)

had low-risk varices,and 12 (14.3%) had high-risk varices.The

median(IQR)time-intervalbetweenEGDandLS/SSmeasurement

was2.5months(1;3).Statisticallysigniﬁcantbetween-group

dif-ferencesweredetectedinINR,conjugatedbilirubinandcreatinine

(p<0.05);MELD(p<0.01);LS,SS,spleenbipolardiameter,spleen

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Table1

Clinical,biochemicalandelastographiccharacteristicsoftheenrolledpopulation(n=210).Continuousvariablesarereportedbymedianandinterquartileranges(IQR).

Patientsarestratiﬁedbypresence(n=84)andabsence(n=126)ofEsophagealVarices.

Variables Altogether

n=210

PatientswithEVs n=84

PatientswithoutEVS n=126 Differences p-values Malesex,n(%) 130(62%) 54(64.3%) 76(60.3%) NS Age(years) 68(57;76) 68(58;76) 66(55;75) NS Etiology,n(%) Viral Alcoholabuse Mixed(viralandalcohol) Others 79(37.6%) 74(35.1%) 9(4.3%) 42(20%) 37(44%) 32(38.1%) 1(1.2%) 14(16.7%) 48(38.1%) 42(33.3%) 8(6.4%) 28(22.2%) NS NS NS NS Portalhypertensivegastropathy

(Grade),n(%) Absent:86 Moderate:117 Severe:7 Absent:16(19%) Moderate:63(75%) Severe:5(6%) Absent:70(55.6%) Moderate:54(42.9%) Severe:2(1.6%) NS

Liverstiffness(kPa) 18.3(13.5;24.7) 23(20;29) 15(12;20) p<0.001

Spleenstiffness(kPa) 34.9(28;46.3) 48(42;57) 29(24;34) p<0.001

Portalveindiameter(cm) 1.24(1.13;1.36) 1.3(1.2;1.4) 1.26±0.21 NS

Portalﬂow(cm/s) 17(15;19) 16(14;19) 17(16;19) NS

Spleenbipolardiameter(cm) 13.1(11.5;14.2) 13.6(12.5;15.2) 12.2(10.8;13.7) p<0.001

Spleenarea(cm2₎ _59.2_(45.7;₇₆₎ ₆₈_(56;₈₅₎ ₅₁_(43;₆₉₎ _p_<_0.001 Weight(kg) 75(65;83.25) 74.5(64;82.5) 75.8(67;85) NS BMI(kg/m2₎ _24.7_(23;_27.8) _24.5_(22.4;_27.3) _25.3_(23;₂₈₎ _NS INR 1.14(1.08;1.23) 1.16(1.08;1.4) 1.13(1.09;1.20) p<0.05 Plateletcount(g/L) 120(92.5;148.25) 93(72;111) 136(118;170) p<0.001 Bilirubin(total)(mg/dL) 0.95(0.7;1.32) 1(0.7;1.4) 0.9(0.7;1.3) NS Bilirubin(conjugated)(mg/dL) 0.23(0.15;0.41) 0.3(0.2;0.5) 0.2(0.2;0.3) p<0.05 Albumin(mg/dL) 3.92(3.6;4.2) 3.9(3.4;4.1) 4(3.7;4.2) NS AST(IU/L) 35(25;51) 35(26;53) 34(25;51) NS ALT(IU/L) 25(17;40) 25(16;35) 26(17;44) NS GGT(IU/L) 63(34.7;120) 65(34;124) 62(35;115) NS Creatinine(mg/dL) 0.8(0.69;0.93) 0.8(0.7;1) 0.8(0.7;0.9) p<0.05

Child–Pughscore,class: A,n(%) B,n(%) 179(85%) 31(15%) 65(77.4%) 19(22.6%) 114(90.5%) 12(9.5%) NS MELD 8(7;10) 9(8;11) 8(7;9) p<0.01 APRI 0.70(0.43;1.18) 1(0.56;1.42) 0.60(0.38;0.92) p<0.001 PSR 904.5(658.65;1337) 665(497;871) 1155(840;1472) p<0.001 LSPS 2.18(1.20;3.57). 3.50(2.42;5.5) 1.38(1;2.35) p<0.001

Statisticallysigniﬁcantdifferencesareexpressedbytwo-tailedp-values.NS:notsigniﬁcant.

Table2

Toobtaintransformedliverstiffnesscalculate:x=liverstiffness(KPa)/10andthentransformedliverstiffnessasx−2_._To_obtain_transformed_spleen_stiffness_calculate:_x₌_spleen

stiffness(KPa)/10andthentransformedspleenstiffnessasx−2_._M#₌_model_number_#;_N₌_number_of_subjects;_AIC₌_Akaike_information_criterion;_BIC₌_Bayesian_information

criterion;ROC-AUC=areaundertheROC-curve;NagelkerkeR2₌_pseudo-R2_._Values_are_regression_{coefﬁcients}_from_logistic_regression_and_95%_conﬁdence_intervals_[in

brackets].Valuesarelogisticregressioncoefﬁcientsand95%CI.

M1 M2 M3 M4 TransformedLS −5.58 [−7.35;3.81]* TransformedSS −81.23 [−104.53;−57.93]* Spleendiameter(cm) 0.32 [0.18;−0.46]* Plateletcount(g/L) −0.04 [−0.05;−0.03] Intercept 1.37 [0.78,1.97]* 5.46 [3.87,7.05]* −4.61 [−6.52,−2.70]* 3.94 [2.64,5.24]* N 210 210 210 210 AIC 232 120 264 214 BIC 239 127 271 221 ROC-AUC 0.79 0.95 0.69 0.83 Pseuro-R2_(Nagelkerke) _0.31 _0.74 _0.14 _0.39 Hosmer–Lemeshow (p-value) 0.57 0.81 0.33 0.00 * _p_<_0.001. 3.1. Modelanalysis

Thefourlogisticregressionmodels(M1toM4)usedtoevaluate

theassociationbetweenvarices(0=no;1=yes)andtransformed

liverstiffness(M1),transformedspleenstiffness(M2),spleen

diam-eter(M3)andplatelets(M4)aregiveninTable2.M2,basedon

transformed spleen stiffness, was the best model according to

alldiscriminativeandcalibrationmetrics(lowestAIC,lowestBIC,

highestAUROC,andhigherPseudo-R2_).

TheplotsinFig.2givetheobservedvs.theexpectedprobability

ofvaricesasestimatedfrommodelsM1toM4.Calibrationisplotted

acrosstenpercentiles(decilesofrisk).Thespikeplotatthebottom

ofthegraphplotsthedistributionofevents(1=presenceofvarices)

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1 M1 Expected Obser v e d Obser v e d Obser v e d Obser v e d Expected Expected Expected M3 M4 M2 .8 .6 .4 .2 0 0 .2 .4 .6 .8 1 0 .2 .4 .6 .8 1 0 .2 .4 .6 .8 1 0 0 0 0 0 .2 .4 .6 .8 1 1 1 1 1 1 .8 .6 .4 .2 0 1 .8 .6 .4 .2 0 0 .2 .4 .6 .8 1

Fig.2. CalibrationplotscorrespondingtomodelsM1–M4.Thespikeplotatthebottomofthegraphplotsthedistributionofevents(1=presenceofvarices)andnon-events

(0=absenceofvarices).

superimposedonthegraphtoallowa roughassessmentofthe

calibrationattheindividuallevel.

3.2. Spleenstiffness

Thecut-offvaluethatallowedustoruleoutthepresenceofEVs

ofanygradewas31kPa.Thisvalueshowedasensitivityof100%,

speciﬁcityof60%,NPVof100%,PPVof62%,accuracyof76%,+LRof

2.47.Onthecontrary,thecut-offvaluethatallowedustoruleinthe

presenceofEVsofanygradewas69kPa.Thiscut-offshowed

sensi-tivityof14%,speciﬁcityof100%,NPVof64%,PPVof100%,accuracy

of65%,+LRof−LRof0.86.Regardinghigh-riskvarices(HRVs),the

cut-offof46kPashowedsensitivityof100%,speciﬁcityof84%,NPV

of100%,PPV27%,+LRof6.19andaccuracyof85%.Fig.3represents

theprobabilityofvaricesaccordingtoSS(A)ascalculatedfrom

model2(M2),thegreyareadeﬁnestheupperandlower95%C.I.of

theprobabilitydeﬁnedbytheblackline.Theprobabilityformula

hasbeenderivedinthreestepsfromvaluesreportedinTable2:

1.CalculationofTransformedSpleenStiffness(TSS):

TSS=

SpleenStiffness (kPa)₁₀

−2

2.CalculationoftheLinearPredictor(LP):

LP_{= (−81.23}_×TSS)₊5_.46

3.Calculation oftheSpleen StiffnessProbabilityIndex (SSPI)of

varicesfromLP:

SSPI=

₁1₋_e

−LP

AccordingtoFig.3,theprobabilityofEVsis<7%withSS

val-ues<30kPa(thisvalueistheﬁrstinﬂection pointofthecurve).

Theslopeofthecurverapidlyincreasesbetween30and50kPa.

In particular, at 40kPa the probability of EVs has seen a

six-fold (around 60%) gain, and at 50kPa the probability is nine

timesgreater(around90%).After50kPatheprobabilitysteadily

increasesandreachesaplateauat70kPa,wheretheprobability

is>97%.

3.3. Liverstiffness

LSshowedanAUROCof0.79(95%C.I.0.72–0.85,p<0.001)to

discriminatethepresenceofEVsofanygrade.SSandLSAUROCs

werecompared,andtheywerefoundtobestatisticallydifferent

(DeLongp<0.001).Thecut-off of20kPashowedasensitivityof

73%,speciﬁcityof78%,NPVof81%,PPVof69%,accuracyof76%,

+LRof3.27,and−LRof0.35.Using20kPaasacut-off,wewould

havemissed5(outof12)HRVs.Fig.3representstheprobability

ofvaricesaccordingtoLS(B)ascalculatedfrommodel1(M1),the

greyareadeﬁnestheupperandlower95%C.I.oftheprobability

deﬁnedbytheblackline.Theprobabilityformulahasbeenderived

(6)

1 .9 .8 .7 .6 .5 .4 .3 .2 .1 0 1720 30 40 50 60 Spleen stiffness

A

B

Probability of v a rices Probability of v a rices Liver stiffness 70 80 90 100 11 20 30 40 50 60 70 73 1 .9 .8 .7 .6 .5 .4 .3 .2 .1 0

Fig.3. Plotstheprobabilityofvaricesaccordingtoliverstiffness(ascalculatedfrommodel1)andspleenstiffness(ascalculatedfrommodel2).Notethattheunitsofthe

x-axisareretransformedtotheoriginalscale,i.e.kPa).

1.CalculationofTransformedSpleenStiffness(TLS):

TLS=

LiverStiffness (kPa)

10

−2

2.CalculationoftheLinearPredictor(LP):

LP= (−5.58×TLS)+1.37

3.CalculationoftheLiverStiffnessProbabilityIndexofvaricesfrom

LP:

LPSI=

1

1−e

−LP

AccordingtoFig.3,apatientwithaLSequalto20kPahasa

probabilityofhavingEVsequalto50%.Moreover,theprobabilityof

havingEVsisbetween0and10%withvaluesofLS=11–12kPa.The

slopeofthecurverapidlyincreasesbetween12and26kPa(where

theprobabilityisequalto60%).Thenthecurvereachesaplateau

at50kPa,andtheprobabilitystabilizesbetween75and80%.

3.4. PSRandLSPS

PSRshowedanAUROCof0.83(95%C.I.0.77–0.88,p<0.001)to

discriminatethepresenceofEVsofanygrade.Thecut-offof909

showedasensitivityof80%,speciﬁcityof70%,NPVof83%,PPVof

64%,accuracyof74%,+LRof2.46,and−LRof0.29.Usingthiscut-off

value,wewouldnothavemissedanyHRVs.LSPSshowedanAUROC

of0.91(95%C.I.0.88–0.95,p<0.001)todiscriminatethepresence

ofEVsofanygrade.Thecut-offof1.72showedasensitivityofa

sen-sitivityof93%,speciﬁcityof62%,NPVof93%,PPVof62%,accuracy

of74%,+LRof2.44,and−LRof0.12.Usingthiscut-offvalue,we

wouldhavemissed1(outof12)HRVs.SSandPSR/LSPSAUROCs

werecompared,andtheywerefoundtobestatisticallydifferent

(DeLongp<0.001).

3.5. ApplicationofBavenoVIcriteria

UsingBavenoVIcriteria,wewouldhavemissed5(outof12)

patientswithHRVs.ThosepatientshadLS<20kPa,butallshowed

SS>46kPa.Forty-ﬁvepatients(21.4%)matchedthecriteriato

rule-outHRVs,and noneofthempresented EVsduringtheEGD.At

the same time, we would have uselessly enrolled for EGD 76

patients(36.1%) who matched thecriteria mentioned aboveto

rule-inHRVs.Twenty-threehadnoendoscopicsignofesophageal

varices,whereas53hadlow-riskvarices.

3.6. CorrelationbetweenSS,LSandplateletcount

A correlationbetweenplatelet countand stiffness

measure-mentswasfound.ThiscorrelationwasstrongerwithSS(r=0.67)

thanLS(r=0.4),p<0.001.InpatientswithSS<31kPa(i.e.,all

with-outEVs)themedian(IQR)valueforplateletcountwas145(IQR

120.5–173.5)g/L,whereasinpatientswithSS>69kPa(i.e.,allwith

EVs)themedian(IQR)valueforplateletwas75(IQR60.5–86.7)

g/L.InpatientswithSS>46kPa,themedian(IQR)valueforplatelet

countwas 86 (IQR66–111) g/L. In patientswithEVs and LS>

20kPa,themedian(IQR)valueforplateletwas87(IQR65–111)

g/L,whereaspatientswithoutEVsandLS<20kPathemedian(IQR)

wassigniﬁcantlyhigher(p<0.001)andequalto170(IQR120–176)

g/L.

3.7. CorrelationbetweenSS,LSandSplenicDimensions

SSshowedahighercorrelationwithbothsplenicdiameterand

splenicarea(r=0.52andr=0.55respectively)ifcomparedtoLS

(r=0.30andr=0.25respectively).InpatientswithSS<31kPa(i.e.

allwithoutEVs)themedian(IQR)valueforspleenbipolardiameter

was12(IQR10–13)cm,whereasthemedian(IQR)spleenarea

mea-suredathilumwas51(IQR43–65)cm2_._In_patients_with_SS_>₆₉_kPa

(i.e.allwithEVs)themedian(IQR)valueforspleenbipolar

diame-terwas15(IQR14–16)cm,whereasthemedian(IQR)spleenarea

measuredathilumwas92(IQR79–94)cm2_.

3.8. LSandSSinhealthyindividualscomparedtoCirrhotic

Patients

Onehundred controlsconsistedof 51 females (51%) and 49

males (49%). Their median (IQR) agewas 52 (IQR 28–56). The

median (IQR) LS and SS values were 4.86 (IQR 4.17;5.59) kPa

and17.50(IQR15.63;20.52)respectively.LSandSSdistribution

between healthy subjects and patients withliver cirrhosis are

reportedinFig.4.

4. Discussion

Livercirrhosisisadiseasecharacterizedbyaprolongedphase

ofcompensation,thatcouldsuddenlyevolvedrastically,shortening

thepatient’ssurvival.Hence,appropriateriskstratiﬁcationin

sub-jectswithcompensateddiseasebecomesessential,anditshould

focusontheidentiﬁcationandcorrectstagingofportal

hyperten-sion.Giventhatthegold-standardtechniquesforthestagingofPH

andthescreeningforEVsareinvasiveandexpensive,researchers

(7)

Healthy subjects 100 80 60 40 20 10 20 30 40 50 60 70

Cirrhotics without EVs

Spleen stiffness (kP a ) Liv er stiffness (kP a)

Cirrhotics with EVs Healthy subjects Cirrhotics without EVs Cirrhotics with EVs

Fig.4. SpleenStiffness(left)andLiverStiffness(right)distributioninHealthySubjects,CirrhoticswithoutEVsandCirrhoticswithEVs.ValuesarereportedinkPa(y-axis).

SpleenStiffnessvalueshavebeenfoundtooverlapbetweenhealthysubjectsandcirrhoticpatientswhohavenotdevelopedEVsyet.Nooverlapwasfoundbetweenliver

stiffnessvaluesinthethreesub-groups.

Elastographyhasattracteda greatdeal ofinterest.Transient

elastography(TE)isanestablishedexcellenttoolforassessingliver

ﬁbrosisandagoodsurrogateforHVPGmeasurement[37].Despite

beingapromisingtool,TEhasseverelimitationsrelativetoSWE

suchas(i)theinabilitytosettheROIinreal-timeandinanoptimal

portionoftheliverparenchyma,(ii)besides,SWEdoesnotrequire

softwaremodiﬁcationstoidentifystiffnessvalue>75kPa,and(iii)

canbeusedeveninpatientswithascites[38].

Despitemachineset-upsinbothhardwareand software,the

rationalebehind thesuperiority ofSS toLSis related toportal

hypertensionpathophysiology.LSincreaseoccursinparalleltothe

riseoftheﬁxeddeterminantofportalpressure,i.e.,intrahepatic

resistances. Therefore, dynamic variations caused by

hyperdy-namicsplanchniccirculationandportal-axisbloodﬂowcannotbe

thoroughlydiscriminatedbyliverelastography[39].Incontrast,

SSrisesprincipallybyspleniccongestion,thateventuallyleadsto

parenchymalﬁbrosisbyarchitecturalchangesandbloodretention

insplenicarteriesandveins[40].Despitethistheoreticalapproach,

severalstudieshavetriedtocorrelatedirectHVPGmeasurement

withbothLSandSS.TheirresultsshowedhowSSstronger

corre-lateswithportalpressure,especiallywithHVPG≥10mmHgand

≥12mmHg.Forexample,Hirookaetal.reportedthatHVPGhada

highergradeofcorrelationwithSS(r=0.85)thanLS(r=0.51)[41].

Besides,ourstudyfoundoutthatSShasastrongercorrelationwith

bothplateletcountandsplenicdimensionsifcomparedtoLS.This

(i)furtherimpliestheverylikelyassociationbetweenSSandthe

pathophysiologyofportalhypertensionand(ii)explainswhy

com-binedscoresuchasPSRanditscombinationwithLS(LSPS)perform

betterthanLSalone.Thesehypothesisandourresultsare

consis-tentwithwhatemergesfromrecentmeta-analyses[42–44],i.e.,LS

byitselfhasadiscriminatorycapabilityofEVsthatisless

perfor-mantthanPSR(ascorewhereonlyplateletandspleendiameterare

present)andLSPS(ascorewherethePSRisstrengthenedbyLS).In

ourgroupofpatients,theAUROCforLS,PSR,andLSPSwhere0.79,

0.83,and0.91respectively.

Afurtherinterestingﬁndingisthecomparisonofstiffness

val-uesbetweencirrhoticsandhealthyvolunteers.Wefoundthatthere

isan overlapofSS valuesbetweenhealthy individuals and

cir-rhoticsubjectswithoutEVs.Similarﬁndingshavebeenpublished

byTakumaetal.[45].Itisverylikelythatthespleenofacirrhotic

patientwithoutEVshasnotyetsufferedfromthe

pathophysiolog-icalmechanismthatpromotedEVsgenesisintheﬁrstplace.The

potentialityofthisﬁndingshouldbefurtherstudiedgiventhefact

thatSShasbeenfoundtopredicthepaticdecompensation[46],and

thereforeitmayhelptodifferentiatebetweentheinitialbuild-up

ofportalpressurefromCSPH.

LShasproventobeauseful,butnotanexcellentdiscriminator

ofEVs,besides,thesuperiorityoftheSSmodelcanbeascribednot

onlyatitsdiscriminativeabilitybuttowardsitscalibration

(high-estAUROCandPseudo-R2_/lowest_AIC_and_BIC)._Before_any_further

discussion,itisimportanttoclarifythat(i)BavenoVIaremeantto

predictHRVs;and(ii)thattheywereestablishedandsafely

appli-cableonTE(ElastPQprotocolinformationontheaforementioned

criteriaisscarce).Inaddition,therateofvariabilitybetween

sys-temsthatuseequivalentelastographictechniquesisintheorder

of12%[47].Thismeansthatresultsderivedfromdifferentstudies

arenotfullyapplicableinothersettingsandevenifthe

concor-dancebetweenTEandElastPQcanbeincreasedbyadherenceto

qualitycriteria [48],theyshouldbeadaptedtoother

elastogra-phytechniques.ApplyingBavenoVIcriteria,wewouldhavemissed

40%ofHRVsandperformedEGDinvainto36%ofourpatients.At

thesametime,BavenoVIcriteriawouldhavesparedEGDsafely

in21%ofpatients.Thissubstantiallylownumberofspared

endo-scopiescouldhavebeenboostedbydirectlyapplyingSScut-off

of31kPa,whichwouldhaveletusspareEGDin36%ofpatients.

OtherstudieswhichusedpSWEhaveproposedseveralcut-offsto

rule-outEVsat3.16–3.18m/s[45,49],whereasstudieswhoused

TEreportedhighervaluesbetween40.8and55kPatorule-outany

varices[17,50–52].OnthesideofHRVs,ourresultsdifferfromwhat

reportedbyBotaetal.[53],Takumaetal.[45]andKimetal.[49],

who reportedcut-offof 2.55m/s, 3.30m/sand 3.40m/s

respec-tively;butareverysimilartowhatreportedbyVermehrenetal.

(4.13m/s)[54].Besides,itisinterestingtohighlight,howourresults

onHRVsareverysimilartoTEcut-off:Colecchiaetal.[55]and

Zykusetal.[56]proposedacut-offof46kPaand47.6kPatorule-in

HRVs–comparabletothevalueof46kPadetectedbyouranalyses.

Despitecut-offanalyses,itwaspossibletocreatea

probabil-itymodel thatcouldhelpdecidetospareendoscopicscreening

inlow-riskpatients(foranygradeofEVs).Havingagiven

prob-abilityinsteadofasinglenumbertorule-inorrule-outaspeciﬁc

eventisindeedmorehelpfulandcouldsupporttheclinicianinthe

decisionofperforminganinvasivetestiftheprobabilityishigh.

Cut-offvalues,eveniftheyarechosentobethemostsensitiveor

speciﬁc,arealwayssubjectstofalse-positivesandfalsenegatives;

and,sometimes,evenwithlowLSandSS,theclinicalpresentation

mayrequiremoreinvasivetests,makingcut-offspointless.

Nev-ertheless,itiswellknownthat(i)EVsdevelopatayearlyrateof

8%incirrhoticpatientswithoutEVsduringtheinitialendoscopic

screening,and(ii)thatpatientswithsmallvaricesmaydevelop

HRVsatayearlyrateof8%[57,58].SSprobabilitymodelmayhelp

todetectthatpercentageofpatientswhowilldevelopvaricesor

progressfromsmalltolargevarices,bymerelycheckingvariation

instiffnessvaluesovertime.

Our studyhas the signiﬁcantstrength of including a

cross-section of patients with compensated disease in whom the

etiologicalfactorhasbeeneliminated,whicharethoseundergoing

repeatedendoscopicsurveillance.Furthermore,weproposea

sim-pleanddirectprobabilitymodelthataimsatindividualizingcare

incirrhoticpatients,thuspotentiallyleadingtobetterrisk

(8)

Thecriticallimitationsofourstudywerethelackofanexternal

validationcohort,theimpossibilityofdirectHVPGmeasurement,

andthesubstantiallownumberofpatientswithHRVs.Inparticular,

thelatterwasrelatedtopatientsbeingadministeredNSBBbefore

beingadmittedtoourcenter.ThelackofHRVsmakesourBavenoVI

analysislessvaluable,butthepracticalapplicationofthesecriteria

wasnotthemainaimofthisstudy.Inaddition,non-invasivecriteria

toruling-outpatientswithHRVsshouldberevisedinthelightofthe

recentpaperpublishedbyVillanuevaetal.[59],whichpointedout

thatevenlow-riskEVs(asamarkerofCSPH),hastobeconsidered

markersofsevereprognosisincirrhoticpatients,andthatNSBB

administrationshouldstartpromptlyregardlessofHRVspresence.

TheseﬁndingschallengethepreviousassumptionthatonlyHRVs

shouldbeconsideredariskfactor,andgivesfurtherstrengthtoour

modelofriskstratiﬁcationforEVsofanygrade.TheSSPI,mainly

basedonlow-riskEVs,couldhelpthecliniciantodecidewhetheror

notinitiateNSBBadministrationinpatientswithahighprobability

ofEVs(i.e.,CSPH)inordertodelayhepaticdecompensationonset.

Inconclusion,theresultsofthisstudyfurtheremphasizethe

potentialclinicalrelevanceofSSmeasurementbypSWE

elastog-raphyintheclinicalworkupofcirrhoticpatients.TheSS(alone

orcombinedwithotherindicators)couldplayacrucialroleasa

screeningtestallowingtheselectionofpatientswithalowriskof

developingvarices,towhomadditionalinvasivetestingshouldbe

avoided. Abbreviations

PH portalhypertension

CSPH clinicallysigniﬁcantportalhypertension

EVs esophagealvarices

DAA directantiviralagents

HVPG hepaticveinpressuregradient

EGD esophagogastroduodenoscopy

HRVs high-riskesophagealvarices

NITs non-invasivetechniques

kPa kilo-Pascal

LS liverstiffness

SS spleenstiffness

PSR plateletcounttospleendiameterratio

LSPS liverstiffness-spleensizetoplateletratioriskscore

cACLD compensatedadvancedchronicliverdisease

NSBB non-selectivebeta-blockers

TIPS transjugularintrahepaticportosystemicshunt

IQR interquantile

M median

AIC Akaikeinformationcriterion

BIC Bayesianinformationcriterion

AUROC areaunderthereceiver-operatingcharacteristiccurve

PPV positivepredictivevalue

NPV negativepredictivevalue

+LR positivelikelihoodratio

−LR negativelikelihoodratio

TSS TransformedSpleenStiffness

TSL TransformedLiverStiffness

LP linearpredictor

SSPI SpleenStiffnessProbabilityIndex

LSPI LiverStiffnessProbabilityIndex

Conﬂictofinterest

Theauthorshavenoconﬂictsofinteresttodeclare.

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