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Contents lists aaila!le at"cience#irect

Best Practice & Research Clinical

Gastroenterology

3

$ariceal an% other ortal hyertension relate%!lee%ing

'anny ron* +#* Clinical Research 'ello,a*

"te-ania Cas* +#* .nternal +e%icine Resi%enta*$irginia /ernn%eGea* +#* Ph#* "ecialist in/eatologya* !* an Carlos GarciaPagn* +#* Ph#* /ea% o-/eatic /eo%ynaic 5nita* !*

Barcelona /eatic /eo%ynaic a!oratory* ier 5nit* .nstitt %e +alalties #igesties i +eta!oli8es*

/osital Clinic* .nstitt %e .nestigacions Bio%i8es :gst Pi i "nyer (.#.B:P")* 5niersity o- Barcelona*Barcelona* "ain

Centro %e .nestigaci;n Bio

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coere%.P" ,ithin 72 h (i%eally 24 h) shol% !e consi%ere%A #ata o

anageent o- gastricariceal !lee%ing is liite%A o clear recoen%ation -or riary rohylaLis can !e %oneA .n acte car%io-n%al ariceal !lee%ing* asoactie agents together ,ithcyanoacrylate (C:) inMection see to !e the treatent o- choiceA'rther C: inMections an%Oor "BB ay !e se% to reent re!lee%i.P" or Balloonoccl%e% retrogra%e transenos o!literation ,hen.P" is contrain%icate% ay !e se% as a resce therayA

Q 2013 =lseier t%A :ll rights resere%A

.ntro%ction

$ariceal !lee%ing is one o- the coonest an% ost seere colications o- lier cirrhosisA =en,ith the crrent !est e%ical care* ortality -ro ariceal !lee%ing is still aron% 20A +oreoer*

ariceal !lee%ing o-ten lea%s to %eterioration in lier -nction* an% it is a coon trigger -or other

colications o- cirrhosis* sch as !acterial in-ections or heatorenal syn%roeA

atral history o- arices in cirrhosis

hen cirrhosis is %iagnose%* arices are resent in a!ot 3040 o- coensate% atients an% in60 o- those ,ho resent ,ith ascites1SAhe annal inci%ence o- ne, arices in those cirrhotic

atients ,ho resent ,ithot is a!ot D102SA: heatic enos ressre gra%ient (/$PG) oer

10 /g is the strongest re%ictor -or the %eeloent o- arices3SA

@nce %eeloe%* the reorte% rate o- rogression -ro sall to large arices is highly aria!le*

ranging -ro D to 30 er year2SAhe -actor that has !een ost consistently associate% ,ith ariceal

rogression is !aseline Chil%Pgh or its ,orsening %ring -ollo,2*4SA@ther -actors ,ere alco

holic etiology o- cirrhosis an% the resence o- re% ,ale arFings2SA.t has !een sho,n that ,hen/$PG %ecreases !elo, 12 /g (either TsontaneosU or case% !y %rg theray or .P") esohagealarices %ecrease in sieDSAhs* an increase% /$PG lays a Fey role !oth in %eeloent an% ro

gression o- the aricesA

@nce arices hae !een %iagnose%* the oerall inci%ence o- ariceal !lee%ing is in the or%er o- 2D at t,o

years6SA$ariceal sie is the ost se-l re%ictor -or ariceal !lee%ing7S*other re%ictors are seerity o-

lier %ys-nction (Chil%Pgh classiEcation) an% the resence o- re% ,ale arFs on the ariceal ,allKSA

hese risF in%icators hae !een co!ine% in the .=C in%eL ,hich allo,s to classi-y atients in %iHerent

gros ,ith re%icte% oneyear !lee%ing risF ranging -ro 6 to 76KSAhe risF o- !lee%ing is ery lo,

(!et,een 1 an% 2) in atients ,ithot arices at the Erst eLaination* an% increases to a!ot D er yearin those ,ith sall arices an% to 1D er year i- e%i or large arices are resent at %iagnosis1SA

Preention o- Erst !lee%ing -ro esohageal arices

"creening -or esohageal arices

he crrent consenss is that eery cirrhotic atient shol% !e en%oscoically screene% -or arices

at the tie o- %iagnosis9Sto %etect those re8iring rohylactic treatentA .n atients ,ithot arices

on initial en%oscoy* a secon% (-ollo,) ealation shol% !e er-ore% a-ter 23 years10SA.n

atients ,ith sall arices* i- !eta!locFers are not initiate%* a -ollo, en%oscoy shol% !e er

-ore% eery 12 years to checF -or a ossi!le increase in sie* !ase% on an eLecte% 101D er year

rate o- rogression o- sall to large aricesA his tie st !e shortene% in case o- clinical %eco

ensationA o -ollo, en%oscoy is nee%e% once !eta!locFers are starte%A#oler5"11Sor transient elastograhy easreents !y E!roscan1214Shae !een roose%

as ossi!le srrogate arFers o- the resence o- esohageal arices !t none has roe% to !e accrate

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"election o- atients -or rohylaLis

+e%i to large arices are consi%ere% high risF arices s!si%iary -or rohylactic treatentA/o,eer* it is ,ell esta!lishe% that sall arices ,ith re% signs on its ,all or Chil%Pgh class C a

tients hae a !lee%ing risF that is siilar to that o- large aricesKSA.n a%%ition* it has !een sggeste%

that !etaa%renergic !locFers ay re%ce the rate o- rogression -ro sall to large arices* an%%ecrease the inci%ence o- ariceal !lee%ing in atients ,ith sall arices9SAhs* crrent gi%elines

recoen% initiating !eta!locFers in atients ,ith e%i to large arices* !t also in atients ,ith

sall arices that ha% re% signs or i- the atient !elong to the Chil%Pgh C class10SA

here is no eHectie treatent to reent the %eeloent o- arices1DSA

reatent -or the reention o- Erst !lee%ing? !etaa%renergic !locFers s en%oscoic !an%ligation

onselectie !etaa%renergic !locFers ("BB) (roranolol or na%olol) hae !een roen eHectiein the reention o- ariceal !lee%ing (-ro 24 to 1D a-ter a e%ian -ollo, 2 years) an% alost

signiEcantly re%ce ortality (-ro 27 to 23)6SA

heray ,ith !etaa%renergic !locFers shol% !e aintaine% in%eEnitely* since ,hen these are ,ith%ra,n the risF o- ariceal heorrhage retrns to ,hat ,ol% !e eLecte% in an ntreate% olation16SA

he a%%ition o- isosor!i%e Dononitrate (."+) increases the /$PG re%ction o- !etaa%renergic

!locFers17SA/o,eer* it is less clear ,hether this translates into a greater clinical e-Ecacy in riary

rohylaLisA :n oen trial sho,e% a lo,er rate o- Erst !lee%ing in atients receiing na%olol I ."+than in those receiing na%olol alone1K*19SA/o,eer* a large* ran%oie%* %o!le!lin% st%y -aile%

to conEr these reslts20SACrrently* in riary rohylaLis it is not recoen%e% this co!ina

tion* neither ."+ a%inistere% aloneA

/o,eer* circa 2D o- cirrhotic atients ,ith high risF esohageal arices ay hae either con

train%ications or cannot tolerate !etaa%renergic !locFersA

=n%oscoic !an% ligation (=B) is eHectie in reenting the Erst ariceal !lee%ing in atients ,ith

e%i to large arices21SAhere is no agreeent on ho, -re8ently arices shol% !e ligate%* theinteral arying -ro eery 1 to eery 4 ,eeFsA @ne trial ealate% the eHectieness an% colications

o- =B eery t,o ,eeFs s eery t,o onths concl%e% that the t,oonth interal schee o!taine%

a higher total era%ication rate an% lo,er recrrence rate22SAhs* althogh a%itte%ly ,eaF* crrent

ei%ence -aors at least onthly interalsA @nce the arices are era%icate%* -ollo, en%oscoies

shol% !e er-ore% at 13 onths an% eery 6 onths therea-ter* an% arices shol% !e re

era%icate% on recrrenceA

"o -ar %iHerent trials hae coare% =B ,ith !eta!locFers -or the riary reention o- ariceal

!lee%ingA he etaanalysis o- these trials sho,s an a%antage o- =B oer !etaa%renergic !locFers in

ters o- reention o- Erst !lee%ing* ,ithot %iHerences in ortality23SAhese reslts* ho,eer*%esere seeral coentsA 'irstly* ost trials ,ere n%ero,ere% or lacFe% any sale sie calc

lationA +oreoer* -or trials ,ere reatrely stoe%2427S*three o- the %e to -tilityA hen

restricting the etaanalysis to trials -lly !lishe% ,ith ore than 100 atients no %iHerences !e

t,een !eta!locFers an% =B ,ere -on%2KSAhs* aaila!le ei%ence to -aor =B oer !eta!locFers

is ery ,eaFA

:nother iortant isse ,hen coaring t,o %iHerent treatent alternaties is the inci%ence o-

a%erse eentsA +ost si%e eHects relate% to !eta!locFers (hyotension* tire%ness* !reathlessness*

iotence* insonia) are easily anage% !y a%Msting the %ose or %iscontining the %rg an% %o not

re8ire hosital a%ission29S*,hile si%e eHects relate% to =B* ostly !lee%ing eiso%es relate% to

the roce%re* -re8ently re8ire% hositaliation* !loo% trans-sion an% een ight lea% to the %eath

o- the atientA

:ccor%ing ,ith this reslts* !eta!locFers are recoen%e% as Erst choice in Chil% : atients ,ith

e%iOlarge arices an% no re% signs* an% either !eta!locFers or =B can !e se% as Erst choice in

atients ,ith higher risF arices10*30SAhe choice o- treatent shol% !e !ase% on local resorcesan% eLertise* atient re-erence an% characteristics* si%e eHects an% contrain%ications10SA

C %il l i l ti ! t !l F ith i t i i l h % i !l F H t th t

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against care%ilol in riary roElaLis sho,ing that care%ilol signiEcantly re%ce% the inci%ence o-ariceal !lee%ing as coare% to =B32SA:nother st%y conErs that the greater re%ction in /$PG

case% !y care%ilol s roranolol (V19 s V12) an% that care%ilol can achiee heo%ynaicresonse (%ecrease /$PG !y ore than 20 or !elo, 120 /g) in a signiEcant gro o- atients

nonreson%ers to roranolol ( to 72 o- heo%ynaic resonse s 39 sing only roranolol)A

Reson%ers to roranolol or care%ilol ha% a lo,er risF o- Erst !lee%ing an% clinical %ecoensationthan nonreson%ers that ,ere treate% ,ith =B33SA

he actal role o- care%ilol in riary rohylaLis still nee%s to !e -rther ealate% !t it ay !e a

goo% alternatie in atients ,ith cirrhosis an% arterial hyertension !ecase it ay ro%ce a greater

re%ction in ean arterial ressre (+:P) than roranololA

Preention o- recrrent !lee%ing -ro esohageal arices

Patients sriing a Erst eiso%e o- ariceal !lee%ing hae a ery high risF o- re!lee%ing an% %eath*then* reention o- recrrent !lee%ing is an%atory10SA

he etaanalysis o- -or aaila!le trials hae sho,n a siilar e-Ecacy reenting re!lee%ing an% in

srial in atients receiing otial en%oscoic treatent (=B) or otiie% haracologicaltreatent (co!ination o- !eta!locFers an% ."+)3437SA: recent etaanalysis sggests that the

co!ination o- %rg theray ,ith =B is ro!a!ly the !est strategy -or reenting ariceal re!lee%ing

3KSA/o,eer* %ata ealating this isse are not ery strongA .n%ee%* t,o trials hae sho,n that the

association o- !etaa%renergic !locFers an% en%oscoic !an% ligation -ares !etter than !an% ligation

alone39*40SA: !eneEcial eHect ,as not conEre% in a thir% st%y41SA.n a%%ition* another t,o trials

-aile% to sho, a clearct !eneEt -ro a%%ing =B to co!ine% haracological theray ,ith

na%olol I .+42*43SA.n the a!sence o- ore st%ies* crrent gi%elines recoen% co!ination

theray (%rgs I =B) -or reenting re!lee%ing10*30SA

.P" in the reention o- re!lee%ing

.P" has roen !etter than the co!ination o- ."+ an% roranolol44S*an% to en%oscoictheray in the reention o- ariceal re!lee%ing4DS*,ith re!lee%ing rates o- 923A /o,eer* the

high eHectieness in reenting recrrent !lee%ing is associate% ,ith an increase% risF o- enceha

loathy* ,ithot a srial !eneEtA Becase o- this* .P" is crrently recoen%e% as resce theray

-or atients ,ho -ail en%oscoic an% haracological treatent -or the reention o- re!lee%ing10SA

.n this in%ication* ncoere% !are .P" has !een coare% ,ith srgical shnts in t,o RCs (K

ortocaal /gra-t shnt in one* an% %istal slenorenal shnt (#"R") in the other)46*47SAhe Erstst%y sho,e% a signiEcantly lo,er re!lee%ing rate in the shnt gro ,ithot %iHerences in srialA

/o,eer* no %iHerences in these araeters ,ere o!sere% in a secon% an% larger trial* althogh at an

eLenses o- a higher reinterention rate in the .P" gro (K2)47SA/o,eer* the o!strction an%

reinterention rates are arFe%ly %ecrease% ,ith the se o- olytetraWoroethylene (P'=)coere%

stents4KSA:ccor%ing to these %ata* .P" sing P'=coere% stents reresents the resce theray o-

choice -or -ailres o- e%ical an% en%oscoic treatentA

he acte !lee%ing eiso%e

Rtre% esohageal arices is the case o- 70 o- all er gastrointestinal !lee%ing eiso%es inatients ,ith ortal hyertension49SA#iagnosis is esta!lishe% at eergency en%oscoy !ase% on

o!sering one o- the -ollo,ing? a) actie !lee%ing -ro a ariL (o!seration o- !loo% srting or ooing

-ro the ariL)X !) ,hite nile or clot a%herent to a ariLX c) resence o- arices ,ithot other o

tential sorces o- !lee%ingA Crrent gi%elines recoen% to er-or en%oscoy ,ithin 12 h a-ter

a%ission* secially in atients ,ith heateesis or heo%ynaic insta!ilityA

General anageent o- the !lee%ing eiso%e incl%es correcting hyooleia an% at reentingcolications associate% ,ith gastrointestinal !lee%ing (!acterial in-ections* heatic %ecoensation*

renal -ailre) ,hich are in%een%ent o- the case o- the heorrhage ('ig 1) .nitial resscitation

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'igA 1A Proose% algorith -or anageent o- esohageal ariceal !lee%ingA

ie%iately secre%* esecially in encehaloatic atients* since the atient is at risF o- !ronchialasiration o- gastric content an% !loo%A his risF is -rther eLacer!ate% !y en%oscoic roce%resA

=n%othracheal int!ation is an%atory i- there is any concern a!ot the sa-ety o- the air,ayA

Bloo% ole relaceent shol% !e initiate% as soon as ossi!le ,ith lasa eLan%ers* aiing at

aintaining systolic !loo% ressre aron% 100 /gA :oi%ing rolonge% hyotension is articlarly

iortant to reent in-ection an% renal -ailre* ,hich are associate% ,ith increase% risF o- re!lee%ing

an% %eathD0SA@ertrans-sion shol% !e aoi%e%* not only !ecase o- the risFs inherent ,ith !loo%

trans-sion* !t also !ecase a restrictie strategy aie% to aintain the heoglo!in leel !et,een 7

an% K gO%l signiEcantly iroe% otcoes in atients ,ith acte er gastrointestinal !lee%ingD1S

eLcet in atients ,ith rai% ongoing !lee%ing or ,ith n%erlying ischeic heart %iseaseA #esite a

roising initial st%yD2S*there is no in%ication -or the se o- r$..a in the treatent o- acte ariceal

!lee%ingD3SA

.n-ection is a strong rognostic in%icator in acte ariceal !lee%ingD4SAhe se o- rohylactic

anti!iotics has !een sho,n to re%ce !oth the risF o- re!lee%ingDDSan% ortalityD6SAhere-ore*

anti!iotics shol% !e gien to all atients -ro a%issionA Yinolones are -re8ently se% (norWoLacin

400 gO!i%) %e to its easy a%inistration an% lo, costD7SA/o,eer* in high risF atients (hyo

oleic shocF* ascites* Man%ice* alntrition) atients ,ith reios 8inolone rohylaLis or in

settings ,ith 8inoloneresistant !acteria iAA ce-triaLone (1 gO%ay) st !e se%DKSA

$ariceal !lee%ing can trigger heatic encehaloathy !t there is no strong %ata to sort the

rohylactic se o- lactlose to reent it10SA

"eciEc theray -or control o- !lee%ing

Pharacological theray

he action o- asoactie %rgs is to re%ce ariceal ressre !y %ecreasing ariceal !loo% Wo,A heselection o- the %rg %een%s on the local resorcesA Recently a eta analysis eLlore% the e-Ecacy o-

i %i i i i l !l %i i l %i 30 i l i h l - 3111 i

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,ith lo,er 7%ay ortality* iroeent in heostasis* lo,er trans-sion re8ireents an% shorter%ration o- hositaliation* ,ith no %iHerences in e-Ecacy in st%ies coaring the %iHerent asoactie

agentsD9SA

$asoressin ,as the Erst %rg se% !t ,as a!an%one% 2D years ago !ecase o- the seerity o- itscar%ioasclar a%erse eentsA he association o- asoressin in-sion ls nitroglycerin reslte% in

enhance% -all in ortal ressre an% less arFe% systeic eHects* an% has !een sho,n to !e oreeHectie an% sa-er than asoressin6SAhis co!ination is still se% in contries ,ere neither ter

liressin nor soatostatin are aaila!le* !t shol% not !e aintaine% -or ore than 4K hors !ecase

o- an increase% inci%ence o- si%eeHectsA

erliressin is a longacting triglycyl lysine %eriatie o- asoressinA Clinical st%ies hae consistently sho,n less -re8ent an% seere si%e eHects ,ith terliressin than ,ith asoressin* (een i-

associate% ,ith nitroglycerin)A

erliressin ay !e initiate% as early as ariceal !lee%ing is ssecte% at a %ose o- 2 gO4hors -or

the Erst 4K h* an% it ay !e aintaine% -or to D %ays at a %ose o- 1 gO4 hors to reent re!lee%ing60SAhe ost coon si%eeHect o- this %rg is a!%oinal ainA "erios si%e eHects sch as e

riheral or yocar%ial ischeia occr in less than 3 o- the atients60SAhe oerall e-Ecacy o- ter

liressin in controlling acte ariceal !lee%ing at 4K hors is o- 7DK0 across trials61S*an% o- 67 atD%ays60SA

"oatostatin is eirically se% as an initial !ols o- 2D04g -ollo,e% !y a 2D04gOh in-sion that isaintaine% ntil the achieeent o- a 24 h !lee%-ree erio%A he !ols inMection can !e reeate% i-

!lee%ing is ncontrolle%A heray shol% !e aintaine% -or to D %ays to reent early re!lee%ing

62SA+inor si%eeHects* sch as nasea* oiting an% hyerglyceia occr in 30 o- atients "o

atostatin has !een sho,n to !e e8ialent to terliressin an% to en%oscoic theray in the control o-

acte ariceal !lee%ing* reention o- early re!lee%ing* ortality or in the inci%ence o- a%erse eents

6SAhe se o- higher %oses o- soatostatin (D004gOh) cases a greater -all in /$PG an% hae !eensggeste% to increase the clinical e-Ecacy in the s!set o- atients ,ith actie !lee%ing at eergency

en%oscoy63SA

@ctreoti%e is a soatostatin analog ,ith longer hal- li-eA he otial %oses are not ,ell %eterine%A.t is sally gien as an initial !ols o- D04g* -ollo,e% !y an in-sion o- 2D or D04gOhA he e-Ecacy o-octreoti%e as a single theray -or ariceal !lee%ing is controersialA /o,eer* RCZs sing octreoti%e

a-ter sclerotheray hae sho,n a signiEcant !eneEt in relation to sclerotheray alone in ters o-

re%cing early re!lee%ing64SA+ortality* ho,eer* ,as not aHecte%6*64SAhese reslts sggest that

octreoti%e ay iroe the reslts o- en%oscoic theray !t has ncertain eHects i- se% aloneA

=n%oscoic theray

Both sclerotheray an% !an% ligation (=B) hae sho,n to !e eHectie in the control o- acte ar

iceal !lee%ingA +etaanalysis sho,s that =B is !etter than en%oscoic inMection sclerotheray (=.") in

the initial control o- !lee%ing* an% is associate% ,ith less a%erse eents an% iroe% srialA

:%%itionally* =."* !t not =B* ay increase ortal ressre6DSAhere-ore =B is the en%oscoic

theray o- choice in acte ariceal !lee%ing* thogh inMection sclerotheray is acceta!le i- !an%

ligation is not aaila!le or technically %i-EcltA =n%oscoic theray can !e er-ore% at the tie o-

%iagnostic en%oscoy* early a-ter a%ission* roi%e% that a sFille% en%oscoist is aaila!leA

Crrent recoen%ations -or initial treatent

he crrent recoen%ation is to start asoactie %rg theray early (i%eally %ring the trans-erralor to arrial to hosital* een i- actie !lee%ing is only ssecte%) an% er-oring =B (or inMection

sclerotheray i- !an% ligation is technically %i-Eclt) a-ter initial resscitation10*30SACrrent

recoen%ation is to aintain %rg theray -or 2D %ays10SA

Resce theraies? taona%e* srgery an% .P"

.n 10 20 o- atients ariceal !lee%ing is nresonsie to initial en%oscoic an%Oor haracologic

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attete%A .- this -ails* or !lee%ing is seere* the atient shol% !e oHere% a %eriatie treatent*!e-ore his clinical stats -rther %eterioratesA

Both .P" an% srgical shnts are eLtreely eHectie controlling ariceal !lee%ingA .P" is Erstchoice* since ost atients re8iring resce treatent hae a%ance% lier %iseaseA .n atients ,ith

sesis* inotroic sort* entilation a-ter asiration* an% %eterioration o- lier an% renal -nction

ortality a-ter .P" laceent is nearly 100A :nyho,* rarely* i- eer* a atient ,ith a Chil%Pgh scoreoer 13 ,ill srie a resce .P"A

: recent trial has sho,n that the er-orance o- an early .P" ,ith a P'=coere% stent in atients

at high risF o- treatent -ailre (%eEne% as Chil% B ,ith actie !lee%ing or Chil% C to 13 oints) ,as

associate% ,ith signiEcant re%ction in the -ailre to control !lee%ing an% in re!lee%ing ,ithot an

increase in encehaloathy rates an% iroing srial in relation to the crrent stan%ar% o- care

66SAhese reslts hae !een conEre% in an o!serational st%y er-ore% inthose centers

articiating in the RC once they a%ote% the early.P" strategy to treat high risF ariceal !lee%ingA

hs* in atients o- high risF o- treatent -ailre* an early .P" ,ithin 72 h (i%eally 24 h) shol% !e

consi%ere%10SA

Balloon taona%e can !e se% as a teoral T!ri%geU (less than 24 h) ntil %eEnite treatent is

institte%* it achiees heostasis in 6090 o- ariceal !lee%ingsA Blee%ing recrs a-ter %eWation inoer hal- o- the cases an% seere colications are coonA Recent %ata sggest that sel-eLan%ing

coere% esohageal etal stent ay !e an alternatie to the "engstaFenBlaFeore !alloon in re

-ractory esohageal ariceal !lee%ing ,ith the a%antage o- less seere colications %esite longer

erio%s o- treatent67*6KSAeertheless* -rther a%e8ately %esigne% trials are re8ire%A

Gastric arices

Gastric arices* %eeloe% in a!ot 20 o- atients ,ith ortal hyertension* are less realent thanesohageal arices an% reresent D10 o- all er %igestie !lee%ing eiso%es in cirrhosis23*69SA

:ccor%ing to "arin70S*gastric arices are classiEe% on gastroesohageal arices (G@$) tye 1 (G@$1)*

the ost -re8ently %etecte% (a!ot 7D o- all gastric arices)* that eLten% along the lesser cratrean% tye 2 (G@$2) that eLten% -ro =$ along the -n%sA .solate% gastric arices (.G$) incl%e .G$1

,hich are those locate% in the -n%s o- the stoach that are also calle% -n%al arices an% .G$2 ,hich

re-er to ectoic arices locate% any,here in the stoach70SAhis classiEcation is releant !ecase risF

o- !lee%ing* treatent an% otcoe o- these tyes o- G$ is %iHerentA /o,eer ost o- the crrent

st%ies %ealing ,ith G$ anageent %o not %iHerentiate !et,een G$ s!tyesA :s -or =$* the res

ence o- re% sots* gastric ariceal sie an% Chil%Pgh class (C [ B [ :) are consi%ere% as risF -actors -orheorrhage69SAG@$2 an% .G$1* sally groe% as car%io-n%al arices* ay !lee% at relatiely lo,

/$PG (1012 /g) ro!a!ly %e to the -act that these arices are sally ery large an% there-ore

their ,all tension (,hich is %eterine% as the ro%ct o- transral ressre an% essel ra%is) ay

reach high ales at a lo,er ressre coare% to esohageal aricesA

he oneyear risF o- G$ !lee%ing has !een reorte% to !e aron% 1016 an% ten%s to !e ore seere*

re8iring o-ten ore trans-sions* an% haing a higher ortality rate then esohageal arices23*70SA

5 to no,* there are not enogh %ata to esta!lish -oral recoen%ations a!ot G$Zs riary ro

hylaLisA :lthogh the e-Ecacy has not !een %eonstrate%* consi%ering its lo, risF* "BB can !e se%A

reatent o- gastric arices

he anageent o- gastric arices still reains a theraetic challenge !ecase o- the liite%n!er o- clinical trials seciEcally %one in these atients71SAGeneral consenss is that the initial

anageent is siilar to that o- esohageal ariceal !lee%ing* incl%ing the se o- rohylactic an

ti!iotics* a care-l relaceent o- oleia ,ith a restrictie trans-sion olicy* an% the early a%in

istration o- asoactie %rgs ('igA2)A

=n%oscoic theray

"eciEc high 8ality %ata on the se o- en%oscoic theray -or acte G$ !lee%ing is liite% an% in

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'igA 2A Proose% algorith -or anageent o- gastric ariceal !lee%ingA

liitations* ost ncontrolle% series reort a high rate o- control o- !lee%ing ,ith the se o- tissea%hesies sch as Cyanoacrylate (C:) ([90)72SA.n a%%ition* sall sie RCs coaring tisse a%

hesies s either =B or =." hae sho,n that tisse a%hesies are e8ally73Sor ore74*7DSeHectie

in the control o- acte !lee%ing an% ore eHectie than !oth in reenting re!lee%ingA G@$1 arices

are sally treate% as esohageal arices ,ith =B* althogh soe inestigators also recoen% the

se o- tisses a%hesies -or G@$1 arices too76SA@n the other han%* en%oscoic theray ,ith tisse

a%hesies* ainly C:* is the recoen%e% theray -or acte !lee%ing -ro .G$1 an% G@$210SABan%

ligation -or sall G@$2 arices ay !e se% i- o!literation ,ith tisse a%hesies is not aaila!le30SA

=." is ineHectie -or the treatent o- the isolate% gastric arices71*77SA

Re!lee%ing rates a-ter an acte G$ !lee%ing eiso%e treate% ,ith tisse a%hesies (ainly C:) range

-ro 7 to 6D ,ith ost o- the large series reorting rates !elo, 1DA hs* a-ter initial heostasis ,ith

tisse a%hesies* reeate% sessions are sally er-ore% on a 2 to 4,eeFly !asis ntil en%oscoic

o!literation is achiee%A "eeral caseseries an% controlle% st%ies hae seciEcally ealate% the eHect o-

long ter inMections o- tisse a%hesies (ainly C:) in or%er to reent G$ re!lee%ingA .n ost o- these

st%ies era%ication is achiee% ,ith 24 inMections ,ith a ole ranging -ro 1 to 2 er sessionA

+ltile colications sch as re!lee%ing %e to eLtrsion o- the gle cast* systeic e!olis*

gastric lcer -oration* aMor gastric ariceal !lee%ing* an% esenteric heatoa associate% ,ith

heoeritone an% !acterial eritonitis* sesis* Estlas an% ericar%itis* chest ain an% %yshagia

hae !een occasionally reorte%7KK2SA"iilar to ,hat occrs ,ith initial heostasis* C: has !een sho,n to !e serior to !oth sclero

h % ! % li i - % h l i h i i h l i

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esohageal (n \ 31) or G$ (G@$ 1 an% G@$ 2)(n \ 10) treate% initially ,ith C: ,ere ran%oie% to

reeate% C: inMections (n \ 21) or roranolol (K0160 g) (n \ 20)K3SAo signiEcant %iHerences,ere o!sere% !et,een the 2 gros in the inci%ence o- ariceal re!lee%ing an% %eathA he inci%ence

o- colications ,as higher in the C: gro (47 sA 10)A : aMor liitation o- the st%y ,as the sall

n!er o- atients ,ith G$K3SA.n a ore recent RC* 67 atients ,ho !le% -ro G$ (D4 G@$ 2 an% 10

.G$1) ,ere allocate% to receie either reeate% C: (n\33) or roranolol (n \ 34) -or secon%aryrohylaLisK4SARe!lee%ing in the C: gro ,as signiEcantly lo,er than in the !eta!locFer gro

(1D s DD* \ 0A004) an% a-ter a 26 onth -ollo, the ortality rate ,as lo,er as ,ell (3 s 2D*

\ 0A026)A he rate o- colications in the C: gro ,as 3A

:n alternatie agent -or en%oscoic treatents is thro!in ,hich conerts E!rinogen to a E!rin

clot* ths -oring a clot insi%e the G$ an% occl%ing !loo% Wo,KDSAhe se o- !oine thro!in ,as!anne% %e to the risF o- otential rion transission !t no, it is aaila!le hanthro!inA =ach

ial is reconstitte% ,ith D o- %istille% ,ater -or a concentration o- 2D0 5OK6SAheaerage %ose

o- inMecte% thro!in ranges !et,een 1D00 an% 2000 5A :aila!le %ata in%icates that thro!in is sa-e

an% eHectie in the treatent o- acte G$ !lee%ing ,ith heostasis rates o- 70100* ho,eer

re!lee%ing rates ay range -ro 7 to D0KD*K791SAo clear %ata hae !een !lishe% regar%ing

-ollo, an% era%ication ratesA :-ter initial heostasis* reeate% thro!in inMections are er-ore%eery 23 ,eeFs ntil era%icationA Gien the acity o- %ata ostly coing -ro case series* the

rotine se o- thro!in cannot !e rotinely recoen%e%A

.P"

.P" is a ery eHectie treatent -or G$ !lee%ing ,ith ore than a 90 sccess rate -or initial

heostasis an% a lo, re!lee%ing rateA hree st%ies coare% the se o- .P" s C: in G$ !lee%ing92

9DSAhese st%ies %eonstrate% no aMor %iHerences in the rate o- initial heostasis !et,een the t,o

theraiesA ,o o- these st%ies93*94Ssho,e% a higher re!lee%ing rate in the C: gro (30 an% D9)

sA the .P" gro (1D an% 40)A 're8ency o- colications ,ere siilar in the t,o gros !t .P"

treate% atients sho,e% a higher inci%ence o- heatic encehaloathy939DSan% longter

or!i%ity re8iring hositaliation94Sthan en%oscoically treate% atientsA he st%ies -on% no

signiEcant %iHerences in srialA .n sary* .P" is a ery eHectie theray to reent G$ re!lee%ingA

eertheless* ore %ata is nee%e% to clari-y the role o- .P" in the secon%ary rohylaLis o- G$

!lee%ing an% %eterine i- this theray st !e niersally alie% or resere% as a resce theray a-ter

-ailre o- ore conseratie aroachesA

"rgery

#eriatie srgery althogh eHectie is rarely se% %e to the ,i%e aaila!ility o- less inasie

techni8es sch as en%oscoy an% interentional ra%iologyA .n selecte% cases* atients ,ith gastric

arices an% segentalOle-tsi%e% ortal hyertension %e to isolate% slenic ein thro!osis ay !e

can%i%ates -or slenectoy or slenic e!oliation as a eans o- %eEnitie theray* ho,eer %ata is

scarceA

Balloonoccl%e% retrogra%e transenos o!literation

"ince its intro%ction !y >anaga,a et al96S*!alloonoccl%e% retrogra%e transenos o!literation

(BR@) has !ecoe ,i%ely accete% in aan an% in soe centers in 5": as a inially inasie an%

highly eHectie treatent -or G$A =thanolaine oleate is the re%oinant an% tra%itional sclerosant

agent se% in the BR@ roce%re* articlarly in :siaA #etergent sclerosants in a -oa or -roth hae

also !een st%ie% in !oth aan (oli%ocanol)97*9KSan% the 5nite% "tates (3 "")99SAGastric arices

sally %isaear a-ter 23 onths (71S)A

he ost coon colications o- BR@ are eigastric an% !acF ain (76)100S*-eer (26)

100*101S*an% transient heatria (D3)A Portal (4A3) an% renal ein thro!osis (D) can !e -on% in a

sall n!er o- atients an% !oth are sally clinically silent102S 103*104SAPlonary e!olis

104S*lonary e%ea97S*coil igration103San% anahylaLis to ethanolaine oleate103Shaealso !een reorte%A

echnical sccess %eEne% !y colete o!literation o- the G$ ,ith sclerosant occrs in 77 100 o-

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!lee%ing a-ter a sccess-l BR@ ranges -ro 0 to 1D or -ro 0 to 31A6 ,hen -actoring in an intenttotreat !asis (incl%ing technical -ailres)A "oe athors sggest that BR@ ight !e !etter than .P"

106Sor gle107Sin the reention o- G$ !lee%ingA /o,eer* the -act that in ost atients treatent

,as a%inistere% as riary rohylaLis -or high risF G$* the st%ies ha% a sall sale sie* an% the

e-Ecacy o- the coaratie gros (either .P" or gle theray) ,as oorer than eLecte%* recl%es

%eEnitie conclsionsA here is only a sall st%y10KSthat ran%oie% 1D atients ,ith acte G$!lee%ing to receie .P" (n \ 7) or BR@ (n \ K) ,ithot o!sering signiEcant %iHerences in there!lee%ing* heatic encehaloathy or srialA

.n contrast to .P"* ,hich is Fno,n to %iert !loo% Wo, -ro heatic arenchya an% ay ,orsenlier -nction in soe atients* sccess-l BR@ theoretically agents er-sion o- the heatic a

renchya an% ay iroe in%ices o- heatic -nctionA @n the other han%* increasing ortal ressre

can case signiEcant aggraation o- ortal hyertensie colications sch as ascites*heatic hy

%rothoraL an% ariceal !lee%ingA .n soe cases* these ro!les ay re8ire s!se8ent.P" lace

ent71SA

.n conclsion* althogh BR@ sees to !e a -easi!le techni8e a!le to sccess-lly control an%

reent G$ !lee%ing* there is a lacF o- goo% 8ality %ata to esta!lish the actal lace o- BR@ on the

anageent o- G$71SABR@ col% !e consi%ere% in atients ,ith G$ !lee%ing an% large gastrorenalshnts that hae contrain%ications -or the se o- .P"A

Portal hyertensie gastroathy an% G:$=

Portal hyertensie gastroathy (P/G) an% gastric antral asclar ectasia (G:$=) are t,o %iHerentclinical con%itions that109S!oth can case chronic gastrointestinal heorrhage in atients ,ith

cirrhosis* ani-este% !y chronic aneiaA

P/G

P/G is the ost -re8ent o- the t,o entities ,ith a realence !et,een 11 an% K0* it is ore o-teno!sere% in atients ,ith ore seere lier %isease110*111San% in atients ,ith cirrhosis ,ho hae

ha% reios en%oscoic treatent ,ith sclerotheray or en%oscoic ariceal ligation112114SAhe

%iagnosis o- P/G is en%oscoic an% it is gra%e% !y acroscoic En%ings as il% (osaicliFe attern)*an% seere (re%oint lesionsOcherryre% sotsO!lacF!ro,n sots)10S*an% is ore o-ten o!sere% in

the -n%s an% cors o- the stoachA he inci%ence o- acte !lee%ing is lo, (less than 3 at 3 years)

,ith a ortality o- 12ADX -or chronic !lee%ing the inci%ence is aron% 101D at 3 yearsA

.n acte !lee%ing* "BB* soatostatin* octreoti%e* assoressin* terliressin* an% estrogens hae

!een roose% !ase% on their a!ility to %ecrease gastric er-sion in this conteLt109SA5 to %ate non

selectie !eta!locFers shol% !e se% in the chronic setting once the acte eiso%e o- !lee%ing is

controlle% an% the atient is sta!le11DSA

.n atients re8iring -re8ent trans-sions* .P" has !een sccess-lly se%109SA

ately it has !een ealate% the se o- argon lasa coaglation (:PC) in the treatent o- P/GA .n asall cohort o- atients ,ith chronic P/G !lee%ing :PC treatent reslte% in a!sence o- er G.

!lee%ing or re%ction o- trans-sion re8ireents in K1 o- atientsA Perhas those atients ,ho %o

not reson% to !eta!locFers* hae seere recrrent !lee%ing an% are not can%i%ates -or .P" col% !e

consi%ere% -or :PC109SA

G:$=

G:$=* also Fno,n as ,aterelon stoach* is en%oscoically characterie% !y re% atches an% sotsin a %iHse or linear %istri!tion in the gastric antrA G:$= is %etecte% less -re8ently coare% to

P/G* haing !een reorte% in only 2116S*o- atients a,aiting lier translantation or 3 o- atients

,ith /C$ an% a%ance% E!rosis111SA@nly 30 o- G:$= cases occr in atients ,ith ortal hyertension eaning that G:$= shol% not !e consi%ere% a ortal hyertensionseciEc -eatreA .n -act*

G:$= can !e o!sere% also in atients ,ith other nonheatic chronic %iseases sch as atoine

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G:$= shol% !e %istingishe% -ro seere P/G117So,ing to their %iHerent resonse to thetreatent o- ortal hyertensionA hile "BB an% .P" can !e se% in seere P/G casing signiEcant

!loo% losses* G:$= is nresonsie to these treatents11KSA

=n%oscoic treatent o- G:$= lesions is the ain treatent -or sytoatic lesions ,hile it is

reasona!le to not treat lesions that are asytoatic109SA:PC is the ost coon se% techni8e

an% it shol% !e reeate% ntil all lesions are -lly treate%A .- en%oscoic theray is not eHectie or it isnot -easi!le* other otions -or ,hich there is ery liite% eLerience can !e consi%ere%A 'e, an% not

ery recent st%ies sggeste% that the se o- estrogenrogesterone ay !e se-l119*120SA"oe

sccess has !een %escri!e% in case reorts ,ith the se o- octreoti%e* corticosteroi%s* traneLaic aci%*

thali%oi%e an% a serotonin antagonist109SA

Practice oints

=n%oscoic screening -or esohageal arices shol% !e er-ore% in eery cirrhotic atientA .t

shol% !e er-ore% eery 23 years in atients ,ithot arices an% eery 12 years i- sallarices are -on% an% !eta!locFers are not initiate%A o -ollo, en%oscoy is nee%e% once

!eta!locFers are starte%A

on selectie !eta!locFers an% =B are !oth eHectie in the reention o- Erst !lee%ingA General anageent o- the !lee%ing eiso%e incl%es care-l !loo% ole relaceent*

secring air,ay* anti!iotic rohylaLis an% early a%inistration o- asoactie %rgsA :n

en%oscoy shol% !e er-ore% ,ithin Erst 12 hA =B is !etter than sclerotheray in theinitial control o- !lee%ingA

=arly.P" sing coere% stents st !e consi%ere% in atients at high risF o- -ailre receiing

the a!oe entione% treatent (Chil% B ,ith actie !lee%ing an% Chil% C to 13)A

Preention o- re!lee%ing is an%atoryA Co!ination theray (%rgs I =B) is recoen%e%A .P" shol% !e consi%ere% as a resce therayA

Gastric arices (G$) reresent D10 o- all er %igestie !lee%ing eiso%es in cirrhosisA

he ost se-l en%oscoic treatent -or acte G$ !lee%ing is tisse a%hesies inMectionA

'rther tisse inMections* "BB or .P" hae !een sho,n to !e eHectie reenting

re!lee%ingA

Balloonoccl%e% retrogra%e transenos o!literation shol% !e consi%ere% in treatent

-ailres an% that are not can%i%ates -or .P"A

Research agen%a

arge longit%inal srey st%ies conEring the role o- =arly.P" in acte ariceal !lee%ingA #eEning a%%itional olations ,ith acte ariceal !lee%ing an% a highrisF o- treatent

-ailre that ay !eneEt -ro =arly.P"A

#eEne the role o- care%ilol in the rohylaLis o- Erst ariceal !lee%ing or re!lee%ingA

.%enti-ying atients at highrisF o- -ailre alying "BB I =B -or the reention o-re!lee%ing that ay !eneEt -ro other ore inasie treatentsA

Coaring ,ith a%e8ately %esigne% trials the se o- sel-eLan%ing esohageal stents s

!alloon taona%e in acte ariceal !lee%ingA

=alation o- "BB in G$ riary rohylaLisA =sta!lish the !est treatent -or acte Gastric ariceal !lee%ing an% -or the reention o- G$

!l %i

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ConWict o- interest stateent

C GarciaPagan receies seaFers -ees -ro G@R=A o other conWicts o- interestA

:cFno,le%gents

"orte% !y a grant -ro the +inisterio %e =conoia y Coetitii%a% (":' 2010O17043) "ainAC.B=Reh% is -n%e% !y the .nstitto %e "al% Carlos ...A

Re-erences

1S#Z:ico GA =sohageal arices? -ro aearance to rtreX natral history an% rognostic in%icatorsA .n? Grosann R*Bosch * e%itorsA Portal hyertension in the 21st centryA #or%recht? >l,er :ca%eic P!lishersX 2004A A 147D4A

2S+erli +* icolini G* :ngeloni "* Rinal%i $* #e ":* +erFel C* et alA .nci%ence an% natral history o- sall esohageal aricesin cirrhotic atientsA /eatol 2003 +arX3K(3)?26672A

3SGrosann R* Garciasao G* Bosch * =scorsell :* GarciaPagan C* Grace #* et alA +lticenter ranoie% lace!o

controlle% trial o- nonselectie !eta!locFers in the reention o- the colications o- ortal hyertension? Enal reslts an% i%entiEcation o- a re%ictie -actorA /eatology 2003X3K("lA 1)?206:A

4S]oli +* +erFel C* +agalotti #* Geli C* Grial%i +* Gatta :* et alA atral history o- cirrhotic atients ,ith sallesohageal arices? a rosectie st%yA : Gastroenterol 2000 'e!X9D(2)?D03KA

DSGrosann R* Bosch * Grace #* Conn /@* Garciasao G* aasa +* et alA /eo%ynaic eents in a rosectie

ran%oie% trial o- roranolol erss lace!o in the reention o- a Erst ariceal heorrhage see coentsSAGastroenterology 1990 oX99(D)?14017A

6S#Z:ico G* Pagliaro * Bosch A Pharacological treatent o- ortal hyertension? an ei%ence!ase% aroachA "einier #is 1999X19(4)?47DD0DA

7S+erFel C* ]oli +* "iringo "* an B/* +agalotti #* :ngeli P* et alA Prognostic in%icators o- risF -or Erst ariceal !lee%ing incirrhosis? a lticenter st%y in 711 atients to ali%ate an% iroe the orth .talian =n%oscoic Cl! (.=C) in%eLA :

Gastroenterol 2000 @ctX9D(10)?291D20A

KS.=CA Pre%iction o- the Erst ariceal heorrhage in atients ,ith cirrhosis o- the lier an% esohageal aricesA : rosectie lticenter st%yA he orth .talian =n%oscoic Cl! -or the "t%y an% reatent o- =sohageal $aricesA =ngl +e% 19KK @ct 13X319(1D)?9K39A

9S+erFel C* +arin R* :ngeli P* ]anella P* 'el%er +* Bernar%inello =* et alA : lace!ocontrolle% clinical trial o- na%olol in therohylaLis o- gro,th o- sall esohageal arices in cirrhosisA Gastroenterology 2004 :gX127(2)?476K4A

10S%e 'RA Reising consenss in ortal hyertension? reort o- the Baeno $ consenss ,orFsho on etho%ology o-%iagnosis an% theray in ortal hyertensionA /eatol 2010 @ctXD3(4)?762KA

11SBerigotti :* Gila!ert R* :!ral%es G* icola C* Br C* Bosch * et alA oninasie re%iction o- clinically signiEcant ortalhyertension an% esohageal arices in atients ,ith coensate% lier cirrhosisA : Gastroenterol 200K +ayX103(D)?11D967A

12S>aei '* >ettaneh :* ZFontcho G* Pinto =* GanneCarrie * rinchet C* et alA ier stiHness easreent selectsatients ,ith cirrhosis at risF o- !earing large oesohageal aricesA /eatol 2006 :gX4D(2)?230DA

13SBrea C* +etiier "* Peron +* Ro!ic +:* Ro8et @* #is =* et alA Prosectie assessent o- lier stiHness -or the noninasie re%iction o- ortal hyertensionA /eatol 2007 an 4X46("1)?"34A

14S$itti '* :rena 5* Roanelli RG* Rega * 'oschi +* Colagran%e "* et alA ier stiHness easreent re%icts seere ortalhyertension in atients ,ith /C$relate% cirrhosisA /eatology 2007 +ayX4D(D)?12907A

1DSGarciasao GA Preenting the %eeloent o- arices in cirrhosisA Clin Gastroenterol 2007 oX41("lA 3)?"3004A

16S:!racinsFas #R* @oF!o R* Grace #* Grosann R* Bosch * Garciasao G* et alA Proranolol -or the reention o- Erstesohageal ariceal heorrhage? a li-etie coitent^ /eatology 2001 #ecX34(6)?1096102A17SGarciaPagan C* 'e '* Bosch * Ro%es A Proranolol coare% ,ith roranolol ls isosor!i%eDononitrate -or ortal

hyertension in cirrhosisA : ran%oie% controlle% st%yA :nn .ntern +e% 1991 +ay 1DX114(10)?K6973A1KS+erFel C* +arin R* =no =* #ona%a C* Caallarin G* or!oli P* et alA Ran%oise% trial o- na%olol alone or ,ith isosor!i%e

ononitrate -or riary rohylaLis o- ariceal !lee%ing in cirrhosisA Grorieneto er Ziertensione ortale (G.P)see coentsSA ancet 1996 #ec 21X34K(9043)?1677K1A

19S+erFel C* +arin R* "acer%oti #* #ona%a C* Caallarin G* or!oli P* et alA ongter reslts o- a clinical trial o- na%olol ,ithor ,ithot isosor!i%e ononitrate -or riary rohylaLis o- ariceal !lee%ing in cirrhosisA /eatology 2000 'e!X31(2)?3249A

20SGarciaPagan * +orillas R+* Ba_ares R* :l!illos :* $illanea C* $ila C* et alA Proranolol ls lace!o s roranolol ls

isosor!i%eDononitrate in the reention o- the Erst ariceal !lee%A : %o!le !lin% RCA /eatology 2003X37?12606A21S.eriale '* Chalasani A : etaanalysis o- en%oscoic ariceal ligation -or riary rohylaLis o- esohageal ariceal

!lee%ingA /eatology 2001 :rX33(4)?K027A22S`oshi%a /* +aa%a `* aniai * `aaoto >* >a,ano `* +igchi `* et alA : ran%oie% control trial o- !ionthly

erss !i,eeFly en%oscoic ariceal ligation o- esohageal aricesA : Gastroenterol 200D "eX100(9)?200D9A23SBosch * :!ral%es G* Berigotti :* GarciaPagan CA Portal hyertension an% gastrointestinal !lee%ingA "ein ier #is

200K 'e!X2K(1)?32DA24S " h F + >l ! G ! # ill t > h $ lt F " hli F t l i ti l l - th i

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2DShlath P* +ahesh,ari :* agannath "* :really :A : ran%oie% controlle% trial o- !eta!locFers erss en%oscoic!an% ligation -or riary rohylaLis? a large sale sie is re8ire% to sho, a %iHerence in !lee%ing ratesA #ig #is "ci200D 'e!XD0(2)?40710A

26Sor!erto * Polese * Cillo 5* Grigoletto '* Brroghs :>* eri #* et alA : ran%oie% st%y coaring ligation ,ithroranolol -or riary rohylaLis o- ariceal !lee%ing in can%i%ates -or lier translantationA ier ransl 2007 +ar16X13?1262A

27Sta!ha R* ensen #+* +artin P* "ai%es * /an "/* Gorn!ein A Ran%oie% st%y coaring !an%ing an% roranolol toreent initial ariceal heorrhage in cirrhotics ,ith highrisF esohageal aricesA Gastroenterology 200D :rX12K(4)?K70K1A

2KSBosch * Berigotti :* GarciaPagan C* :!ral%es GA he anageent o- ortal hyertension? rational !asis* aaila!letreatents an% -tre otionsA /eatol 200KX4K("lA 1)?"6K92A

29SGarciaPagan C* Bosch A =n%oscoic !an% ligation in the treatent o- ortal hyertensionA at Clin Pract Gastroenterol/eatol 200D oX2(11)?D263DA

30SGarciasao G* "anyal :* Grace #* Carey A Preention an% anageent o- gastroesohageal arices an% aricealheorrhage in cirrhosisA /eatology 2007 "eX46(3)?9223KA

31SBanares R* +oitinho =* +atilla :* GarciaPagan C* areae * Piera C* et alA Ran%oie% coarison o- longtercare%ilol an% roranolol a%inistration in the treatent o- ortal hyertension in cirrhosisA /eatology 2002X36?136773A

32Sriathi #* 'ergson * >ochar * eithea% :* heraon%os G* +c:oy C* et alA Ran%oie% controlle% trial o- car

e%ilol erss ariceal !an% ligation -or the reention o- the Erst ariceal !lee%A /eatology 2009 "eXD0(3)?K2D33A33SRei!erger * 5l!rich G* 'erlitsch :* Payer B:* "ch,a!l P* Pinter +* et alA Care%ilol -or riary rohylaLis o- ariceal

!lee%ing in cirrhotic atients ,ith haeo%ynaic nonresonse to roranololA Gt 2012 #ec 1KA34S$illanea C* +inana * @rti * Gallego :* "oriano G* orras * et alA =n%oscoic ligation coare% ,ith co!ine%treatent ,ith na%olol an% isosor!i%e ononitrate to reent recrrent ariceal !lee%ingA =ngl +e% 2001 :g 30X34D(9)?647DDA

3DSPatch #* "a!in C:* Golis * Gern%a G* Greensla%e * +erFel C* et alA : ran%oie%* controlle% trial o- e%ical therayerss en%oscoic ligation -or the reention o- ariceal re!lee%ing in atients ,ith cirrhosisA Gastroenterology 2002@ctX123(4)?10139A

36So G/* Chen C* Chen +/* /s P.* in C>* sai * et alA Ban%ing ligation erss na%olol an% isosor!i%e ononitrate -orthe reention o- esohageal ariceal re!lee%ingA Gastroenterology 2002 "eX123(3)?72K34A

37SRoero G* >raet #* :rgon * $lcano C* "are :* 'assio =* et alA Coaratie st%y !et,een na%olol an% Disosor!i%eononitrate sA en%oscoic !an% ligation ls sclerotheray in the reention o- ariceal re!lee%ing in cirrhotic atients?a ran%oie% controlle% trialA :lient Pharacol her 2006 :g 1DX24(4)?60111A

3KSGonale R* ]aora * GoeCaarero * +olinero +* Banares R* :l!illos :A +etaanalysis? co!ination en%oscoican% %rg theray to reent ariceal re!lee%ing in cirrhosisA :nn .ntern +e% 200K l 1DX149(2)?10922A

39So G/* ai >/* Cheng "* Chen +/* /ang /C* /s P.* et alA =n%oscoic ariceal ligation ls na%olol an% scral-ate

coare% ,ith ligation alone -or the reention o- ariceal re!lee%ing? a rosectie* ran%oie% trialA /eatology 2000"eX32(3)?461DA

40S%e la Pena * Brllet =* "anche/ernan%e =* Riero +* $ergara +* +artinorente * et alA $ariceal ligation ls na%ololcoare% ,ith ligation -or rohylaLis o- ariceal re!lee%ing? a lticenter trialA /eatology 200D +arX41(3)?D72KA

41S>ar :* ha ">* "hara P* #!ey "* yagi P* "hara BC* et alA :%%ition o- roranolol an% isosor!i%e ononitrate toen%oscoic ariceal ligation %oes not re%ce ariceal re!lee%ing inci%enceA Gastroenterology 2009 "eX137(3)?K92901A

42SGarciaPagan C* $illanea C* :l!illos :* Banares R* +orillas R* :!ral%es G* et alA a%olol ls isosor!i%e ononitratealone or associate% ,ith !an% ligation in the reention o- recrrent !lee%ing? a lticenter ran%oie% controlle% trialAGt 2009 'e! 12XDK(K)?1144D0A

43So G/* Chen C* Chan //* sai * /s P.* in C>* et alA : ran%oie%* controlle% trial o- !an%ing ligation ls %rgtheray erss %rg theray alone in the reention o- esohageal ariceal re!lee%ingA Gastroenterol /eatol 2009 nX24(6)?9K27A

44S=scorsell :* Banares R* GarciaPagan C* Gila!ert R* +oitinho =* Pi8eras B* et alA .P" erss %rg theray in reentingariceal re!lee%ing in a%ance% cirrhosis? a ran%oie% controlle% trialA /eatology 2002 'e!X3D(2)?3KD92A

4DSBrroghs :>* $angeli +A ransMglar intraheatic ortosysteic shnt erss en%oscoic theray? ran%oie% trials-or secon%ary rohylaLis o- ariceal !lee%ing? an %ate% etaanalysisA "can% Gastroenterol 2002 +arX37(3)?249D2A

46SRosergy :"* "eraEni '+* ],ei!el BR* BlacF * >%ryF B* or% /* et alA ransMglar intraheatic ortosysteic shntsA sall%iaeter rosthetic /gra-t ortacaal shnt? eLten%e% -ollo, o- an eLan%e% ran%oie% rosectietrialA Gastrointest "rg 2000 oX4(6)?DK997A

47S/en%erson +* Boyer #* >tner +/* RiFFers * eHers * :!=lag% >A #"R" s .P" -or re-ractory ariceal !lee%ing? arosectie ran%oie% controlle% trialA /eatology 2004X40("lA 1)?72D:A

4KSBrea C* GarciaPagan C* @tal P* Poierayrarges G* Cha!!ert $* Corte C* et alA .roe% clinical otcoe singolytetraWoroethylenecoate% stents -or tis? reslts o- a ran%oie% st%yA Gastroenterology 2004 'e!X126(2)?4697DA

49S#Z:ico G* %e 'ranchis RA 5er %igestie !lee%ing in cirrhosisA Posttheraetic otcoe an% rognostic in%icatorsA/eatology 2003 "eX3K(3)?D99612A

D0SCar%enas :* Gines P* 5ri * Bessa * "aleron +* +as :* et alA Renal -ailre a-ter er gastrointestinal !lee%ing incirrhosis? inci%ence* clinical corse* re%ictie -actors* an% shortter rognosisA /eatology 2001 @ctX34(4 Pt 1)?6716A

D1S$illanea C* Coloo :* Bosch :A rans-sion -or acte er gastrointestinal !lee%ingA =ngl +e% 2013 :r 4X36K(14)?13623A

D2SBosch * ha!t #* Ben%tsen '* #Z:ico G* :l!illos :* Gonale :* et alA Reco!inant -actor $..a -or er gastrointestina!lee%ing in atients ,ith cirrhosis? a ran%oie%* %o!le!lin% trialA Gastroenterology 2004 @ctX127(4)?112330AD3SBosch * ha!t #* :l!illos :* Car!onell * "icaF * +assar% * et alA Reco!inant 'actor $..: (R'$..:) -or actie ariceal

!lee%ing in atients ,ith a%ance% cirrhosis? a lticentre ran%oie% %o!le!lin% lace!ocontrolle% trial /eatol

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DDS/o +C* in /C* i * >o B.* ee '`* Chang '`* et alA :nti!iotic rohylaLis a-ter en%oscoic theray reentsre!lee%ing in acte ariceal heorrhage? a ran%oie% trialA /eatology 2004 +arX39(3)?746D3A

D6SBernar% B* Grange #* >hac =* :iot * @olon P* Poynar% A :nti!iotic rohylaLis -or the reention o- !acterialin-ections in cirrhotic atients ,ith gastrointestinal !lee%ing? a etaanalysisA /eatology 1999 nX29(6)?16DD61A

D7SRiola :* Garciasao G* aasa +* Pi%%ocF * Planas R* Bernar% B* et alA #iagnosis* treatent an% rohylaLis o-sontaneos !acterial eritonitis? a consenss %ocentA .nternational :scites Cl!A /eatol 2000 anX32(1)?142D3ADKS'ernan%e * Ri %:* Goe C* #ran%e R* "erra%illa R* Garner C* et alA orWoLacin s ce-triaLone in the rohylaLis o-

in-ections in atients ,ith a%ance% cirrhosis an% heorrhageA Gastroenterology 2006 @ctX131(4)?1049D6AD9Sells +* Chan%e * :%as P* Beaton +* estiF +* Boyce =* et alA +etaanalysis? asoactie e%ications -or the an

ageent o- acte ariceal !lee%sA :lient Pharacol her 2012 nX3D(11)?12677KA60S=scorsell :* Ri %:* Planas R* :l!illos :* Banares R* Cales P* et alA +lticenter ran%oie% controlle% trial o- terliressin

erss sclerotheray in the treatent o- acte ariceal !lee%ing? the =" st%yA /eatology 2000 "eX32(3)?4716A61S.oanno G* #ost * RocFey #CA "ysteatic reie,? terliressin in acte oesohageal ariceal haeorrhageA :lient

Pharacol her 2003 anX17(1)?D364A62S=scorsell :* Bor%as +* %el :r!ol R* araillo * Planas R* Banares R* et alA Ran%oie% controlle% trial o- sclerotheray

erss soatostatin in-sion in the reention o- early re!lee%ing -ollo,ing acte ariceal heorrhage in atients ,ithcirrhosisA $ariceal Blee%ing "t%y GroA /eatol 199K oX29(D)?779KKA

63S+oitinho =* Planas R* Ba_ares R* :l!illos :* Ri%el:r!ol * Gale C* et alA +lticenter ran%oie% controlle% trialcoaring %iHerent sche%les o- soatostatin in the treatent o- acte ariceal !lee%ingA /eatol 2001X3D(6)?712KA

64SCorley #:* Cello P* :%Fisson * >o '* >erliFo,sFe >A @ctreoti%e -or acte esohageal ariceal !lee%ing? a etaanalysisA Gastroenterology 2001 +arX120(4)?946D4A6DS:gerinos :* :ronis :* "te-ani%is G* +atho * $lachogiannaFos * >ogiotian :* et alA "staine% rise o- ortal

ressre a-ter sclerotheray* !t not !an% ligation* in acte ariceal !lee%ing in cirrhosisA /eatology 2004 nX39(6)?162330A

66SGarciaPagan C* Caca >* Brea C* alean * :enro%t B* ca :* et alA =arly se o- .P" in atients ,ith cirrhosis an%ariceal !lee%ingA =ngl +e% 2010 n 24X362(2D)?23709A

67S/!ann R* Bo%laM G* Coo +* BenFo * Pichler P* :l >athi! "* et alA he se o- sel-eLan%ing etal stents to treatacte esohageal ariceal !lee%ingA =n%oscoy 2006 "eX3K(9)?K96901A

6KS=scorsell :* Bosch A "el-eLan%a!le etal stents in the treatent o- acte esohageal ariceal !lee%ingA GastroenterolRes Pract 2011X2011?9109K6A

69SBerigotti :* "eiMo "* Reerter =* Bosch A :ssessing ortal hyertension in lier %iseasesA =Lert Re Gastroenterol /eatol2013 'e!X7(2)?141DDA

70S"arin ">* ahoti #* "aLena "P* +rthy "* +aF,ana 5>A Prealence* classiEcation an% natral history o- gastric arices? alongter -ollo, st%y in D6K ortal hyertension atientsA /eatology 1992 #ecX16(6)?13439A

71S/ashie +* :Fahoshi * oiFa,a +A +anageent o- gastric aricesA Gastroenterol /eatol 2011 anX26("lA 1)?102KA

72S/ang /* eh /]* Chen G/* Chang C"* C`* Poon ">* et alA =n%oscoic treatent o- !lee%ing gastric arices !y !tyl2 cyanoacrylate (histoacryl) inMection? longter e-Ecacy an% sa-etyA Gastrointest =n%osc 2000 :gXD2(2)?1607A

73San PC* /o +C* in /C* i * ee '`* Chang '`* et alA : ran%oie% trial o- en%oscoic treatent o- acte gastricariceal heorrhage? !tyl2cyanoacrylate inMection erss !an% ligationA /eatology 2006 :rX43(4)?6907A

74So G/* ai >/* Cheng "* Chen +/* Chiang /A : rosectie* ran%oie% trial o- !tyl cyanoacrylate inMection erss!an% ligation in the anageent o- !lee%ing gastric aricesA /eatology 2001 +ayX33(D)?10604A

7DS@ho >* .,ao * "ino +* oyonaga :* aniFa,a >A =thanolaine oleate erss !tyl cyanoacrylate -or !lee%ing gastricarices? a nonran%oie% st%y see coentsSA =n%oscoy 199D nX27(D)?349D4A

76So G/* ai >/A "hol% G@$1 !e treate% as -or esohageal arices^ Gastroenterology 2004 "eX127(3)?1014DA77S>orla * Ralls PA he eHects o- chronic en%oscoic ariceal sclerotheray on ortal ressre in cirrhoticsA Gastroenter

ology 1991 "eX101(3)?K00DA7KSCheng '* ang ]Y* i C]* in * `eo :=* in BA o, inci%ence o- colications -ro en%oscoic gastric ariceal o!t

ration ,ith !tyl cyanoacrylateA Clin Gastroenterol /eatol 2010 "eXK(9)?7606A

79SBattaglia G* +or!in * Patarnello =* +erFel C* Corona +C* :ncona =A $isceral Estla as a colication o- en%oscoictreatent o- esohageal an% gastric arices sing iso!tyl2cyanoacrylate? reort o- t,o casesA Gastrointest =n%osc2000 :gXD2(2)?26770A

K0SGreen,al% B#* Cal%,ell "/* /esenhei%e ==* Patrie * illias * Binoeller >'* et alA 2!tylcyanoacrylate -or!lee%ing gastric arices? a 5nite% "tates ilot st%y an% cost analysisA : Gastroenterol 2003 "eX9K(9)?19K2KA

K1San `+* Goh >* >aarlaan :* an P"* RanMee P* "ale @* et alA +ltile systeic e!oliss ,ith seticeia a-tergastric ariceal o!literation ,ith cyanoacrylateA Gastrointest =n%osc 2002 'e!XDD(2)?276KA

K2SChen ``* "hen C* "oon +"* ai /A i-ethreatening ericar%itis a-ter !tyl2cyanoacrylate inMection -or esohagealariceal !lee%ing? case reortA Gastrointest =n%osc 200D +arX61(3)?4K79A

K3S=rar% "* #oncea +* #elhaye +* Golstein P* #eiere * e +@A =n%oscoic histoacryl o!literation sA roranolol inthe reention o- esohagogastric ariceal re!lee%ing? a ran%oie% trialA =n%oscoy 2003 "eX3D(9)?7293DA

K4S+ishra "R* Chan%er "B* >ar :* "arin ">A =n%oscoic cyanoacrylate inMection erss !eta!locFer -or secon%ary rohylaLis o- gastric ariceal !lee%? a ran%oise% controlle% trialA Gt 2010 nXD9(6)?7293DA

KDS`ang * riathi #* heraon%os G* o%% :* /ayes PCA =n%oscoic se o- han thro!in in !lee%ing gastric aricesA

: Gastroenterol 2002 nX97(6)?13K1DAK6S+c:oy C* Pleris * /ayes PCA /an thro!in -or the treatent o- gastric an% ectoic aricesA orl% Gastroenterol2012 o 7X1K(41)?D9127A

K7S >rystallis C +c:oy C ilson /ayes PC Pleris =5"assiste% thro!in inMection -or ectoic !lee%ing aricesa

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K9S/eneghan +:* Byrne :* /arrison P+A :n oen ilot st%y o- the eHects o- a han E!rin gle -or en%oscoic treatento- atients ,ith acte !lee%ing -ro gastric aricesA Gastrointest =n%osc 2002 "eXD6(3)?4226A

90SPreioslo R* +cair :* illias RA hro!in is eHectie in arresting !lee%ing -ro gastric ariceal heorrhageA #ig#is "ci 1999 :rX44(4)?77KK1A

91Sillias "G* Peters R:* esta!y #A hro!inan eHectie treatent -or gastric ariceal haeorrhageA Gt 1994 "eX3D(9)?12K79A92Sriathi #* heraon%os G* acFson =* Re%hea% #* /ayes PCA he role o- the transMglar intraheatic ortosysteic

stent shnt (.P"") in the anageent o- !lee%ing gastric arices? clinical an% haeo%ynaic correlationsA Gt 2002:gXD1(2)?2704A

93S+aha%ea "* Bellay +C* >essel #* #aies +/* +illson C=A CosteHectieness o- !tyl2cyanoacrylate (histoacryl)gle inMections erss transMglar intraheatic ortosysteic shnt in the anageent o- acte gastric ariceal!lee%ingA : Gastroenterol 2003 #ecX9K(12)?26KK93A

94SProcaccini * :l@saii :+* orth P* :rgo C* Cal%,ell "/A =n%oscoic cyanoacrylate erss transMglar intraheaticortosysteic shnt -or gastric ariceal !lee%ing? a singlecenter 5A"A analysisA Gastrointest =n%osc 2009 oX70(D)?KK1

9DSo G/* iang /* Chen C* Chen +/* ai >/* /s P.* et alA : rosectie* ran%oie% controlle% trial o- transMglarintraheatic ortosysteic shnt erss cyanoacrylate inMection in the reention o- gastric ariceal re!lee%ingA=n%oscoy 2007 :gX39(K)?679KDA

96S>anaga,a /* +ia "* >oyaa /* Gotoh >* 5chi%a * @F%a >A reatent o- gastric -n%al arices !y !alloonoccl%e%retrogra%e transenos o!literationA Gastroenterol /eatol 1996 anX11(1)?D1KA

97SChoi "`* on `* >i >:* ee %`* ee >/A 'oa sclerotheray sing oli%ocanol -or !alloonoccl%e% retrogra%etransenos o!literation (BR@)A =r Ra%iol 2011 anX21(1)?1229A9KSCleents * Caanagh >* :li '* >ano%ias /* >e * Ro!erts "* et alA $ariant treatent -or gastric arices ,ith

oli%ocanol -oa sing !alloonoccl%e% retrogra%e transenos o!literation? a ilot st%yA +e% .aging Ra%iat @ncol2012 #ecXD6(6)?D9960DA

99S"aa% =A he history an% eoltion o- !alloonoccl%e% retrogra%e transenos o!literation (BR@)? -ro the 5nite%"tates to aan an% BacFA "ein .nterent Ra%iol 2011 "eX2K(3)?2K37A

100S/iraga * :iFata /* aFaFi "* >o%aa /* "hiraFa,a /* .ara +* et alA he longter otcoe o- atients ,ith !lee%inggastric arices a-ter !alloonoccl%e% retrogra%e transenos o!literationA Gastroenterol 2007 :gX42(K)?66372A

101S:Fahoshi * oiFa,a +* >aori +* stsi * agao `* /ashie +* et alA .act o- !alloonoccl%e% retrogra%etransenos o!literation on anageent o- isolate% -n%al gastric ariceal !lee%ingA /eatol Res 2012 :rX42(4)?3KD93A

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occl%e% retrogra%e transenos o!literation sing so%i tetra%ecyl sl-ate -oaA $asc .nter Ra%iol 2011 +arX22(3)?30916A

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