66904554

7/28/2019 66904554

1/22

1DOI10.3233/DMA-2011-0836IOSPress

Prognosticmarkersinpatientswithascites andhepatorenalsyndrome

LeylaNazala andAndresCardenasb,Gastroenterology Department, Air Force Hospital, Santiago,Chile

GI/EndoscopyUnit, Institut de Malalties Digestives i Metaboliques,Hospital Clnic, University of

Barcelona,Spain

1. Introduction

Cirrhosisisaprogressiveliverdisordercharacterizedbyadistortedliverarchitectureduetobrosiswhicheventuallyleadstoportalhypertension.Itisacommon

causeofmortalityaccountingforover26,000deaths annuallyintheUnitedStates[1].Thenaturalcourseofpatientswithcirrhosisisfrequentlycomplicatedbytheaccumulationofuidintheperitonealspaceinthe formofascites.Thisiscausedbyanabnormalregu-lationofextracellularuidvolumewhichleadstoal-terationsinrenalfunctionwithrenalsodiumretention, solute-freewaterretention,andrenalvasoconstriction.Thesechangesareresponsibleforuidaccumulati

onintheformofascites,dilutionalhyponatremiaandhep- atorenalsyndrome(HRS)respectively.Ascitesisthemostcommoncomplicationofcirrhosisandposesandincreasedriskforinfections,renalfailureandmortal- ity. Patients with cirrhosis and ascites have apoorprognosisanditisestimatedthatnearlyhalfoftheseindividualswilldieinapproximately5yearswithoutlivertransplantation.HypervolemichyponatremiaandHRSoccurlaterandconferanevenaworseprognosis.Thisarticlereviewscommonprognosticmarkersan

mic hyponatremiaandHRS.

7/28/2019 66904554

2/22

calaccumulationoffreeuidintheperitonealcavity.Thedevelopmentofascitesinapatientwithcirrhosisdenesamileston

easitisaconditionassociatedwithpoorprognosis.Pa-tientswithcompensatedcirrhosishavea30%riskofdevelopingascitesat5years.Thosethatdevelopas-citeshaveaprobabilityofsurvivalof85%at1yearand56%at5yearsiftheydonotreceivelivertrans-plantation[2].However,individualsurvivalvariesac-cordingtothedegreeofsodiumretention,responseto

diureticsorassociatedcomplications(i.e.hemorrhage, infectionsorhepatocellularcarcinoma).Itisconsid-

eredthatpatientswitharstonsetofasciteshavebt- ter survivalthan thosewithpreviousepisodesof ascites[3].Additionally,patientswithmildtomoderate

ascites(whohavegoodresponsetotreatment)haveabetterprognosisthanpatientswithrefractoryascites. The developmentof refractory ascites,characterizedbyaninabilitytoresolveasciteswithstandardmedcaltreatment,isassociatedwithshorttermmortaliy andisamarkerofpoorprognosiswithsurvivalrate of about50% at oneyear [4]. Anumberof factorsassociatedwithpoorprognosishavebeenidentiedin patientswithcirrhosisandascites(Table1).

Themostimportantfactorsinthepredictionofpoorprognosis

? Correspondingauthor:AndresCardenas,MD,MMSc,GIUnit/ arehighChild-Pughscores,increasedserumcreatinine,

InstitutdeMalaltiesDigestivesiMetaboliques,UniversityofBarce-lona, Hospital Clinic Villarroel 170, Esc32,08036Barcelona,

-

hyponatremia,intensesodiumretention(urinesodiumlessthan10mEq/day),andlowarterialpress

ISSN0278-0240/11/$27.50 2011IOSPressandtheauthors. Allrightsreserved

7/28/2019 66904554

3/22

140

7/28/2019 66904554

4/22

epatore nal syndrome

7/28/2019 66904554

5/22

ease. Furthermore,ithasbeendescribedthatascitesrelatedvariablessuchastheasciticuidproteincon-

Table1

centrationandpreviousepisodesofspontaneousbac-terialperitonitis(SBP)addprognosticinformationto theChildPughScore[4,6]. Alowtotalproteincon-

centrationintheasciticuid( 1.5mg/dl(20).

Renalfunctionasassessedwithserumcreatinineisanimportantmakerofprognosisinpatientswithadvancedcirrhosis.Infactthecurrentallocationsystemoflivertransplantationin

theUnitedStatesandothercountriesincludesserum creatinineasavariableintheModelforEndStageLiv-

7/28/2019 66904554

8/22

. Renal functioncanbeestimatedbyassessingglomerularltrationrate

(GFR)eitherwiththeserumcreatininelevel,formulas thatestimate GFR, ordirectclearancemethodswithexogenousmarkers(2123).HoweverthemostwidelyusedparametertoestimateGFRinclinicalpracticeisserumcreatinine(21).Slightincreasesinserumcreati-nine(from1.2to1.5mg/dl)areindicativeofreductionsinGFRandareassociatedwithreducedsurvival.Ho

w-ever,serumcreatinineishighlyinuencedbyfactorssuchasdecreasedmusclemassandproteinintake,soitcanoverestimaterenalfunctioninpatientswithcir-rhosis[22,23].Overestimationofrenalfunctionoccurs moreofteninpatientswithaverylowGFR.Theetiologyofrenalinsufciencyinpatientswithcirrhosisalsohasaprognosticvalueinpatientswith

cirrhosis[24].Themostcommoncausesofrenalfail-ureinthesepatientsarebacterialinfectionsandvo

-umedepletioncausedbybleedingoruidlosses.Dug inducedrenalfailure(mainlyfromnon-steroidalanti-inammatorydrugs(NSAIDs)andintrinsicrenaldis-eases(mainlyglomerulardiseaseassociatedwithlco-holicliverdisease,hepatitisBorCinfectionorotherchronickidneydiseases)arelesscommoncauses.Inarecentprospectivestudyof562patientsadmitted

totertiaryhospitalfordecompensatedcirrhosisina6yearperiod[24],themostfrequentcauseofrenaldysfunc-tionwasrenalfailureassociatedwithinfections,main- lySBP(46%),followedbyhypovolemia-relatedrenalfailure(32%),HRS(13%),andparenchymalnephropa- thy(9%). The3-monthprobabilityofsurvivalforall

7/28/2019 66904554

9/22

142

7/28/2019 66904554

10/22

epatore

nal

syndro

me

Table2

Childpughclassicationandmodelforend-stageliverdiseasemodelMELD Child-

PughClassication

1 2 3 Ascites Absent Mild Moderate Encephalopathy Absent 12

Bilirubinmg/dL < 223 >

7/28/2019 66904554

11/22

Bilirubinmg/dL 10Albumingr/L >3,5 2,83,5

7/28/2019 66904554

12/22

respectively[2].InpatientswithrefractoryascitesorHRS, this proportion may increase up to 50%

[26].

ticvalue,particularlythosethatthattakeintoaccountrenalandcirculatoryfunctionhavebeenide

ntiedin

7/28/2019 66904554

13/22

L.NazalandA.Cardenas/Prognosticmarkersinpatients withascitesandhepatorenal syndrome 143awaterload,meanarterialpressure,Child-Pughclass,

andserumcreatinine)hasbeenproposed,howeverthis test hasnotgainedacceptanceandmaynotbeeasi- lyapplicableinallcenters[9].Forseveraldecades, theChild-Pughclassicationhasbeenusedinclinicalpracticeto estimatesurvivalof patientswithascites.Thisclassicationwasoriginallydesignedtoestimatetheriskofdeathincirrhoticpatientssubmittedtosurgi-calportosystemicshuntsforthetreatmentofportal

hy- pertension[30,33,34].Thissystemincludesvariablessuchasascites,encephalopathy,serumbilirubin,serum albumin,andprothrombintime.Subsequenttoitsap-plicationtoestimatesurgicalrisk,theuseofChild-Pugh classicationwasvalidatedandextendedtoevaluate long-termprognosisofcirrhosis[35,36].Thesimplici-tyoftheChild-Pughclassicationdetermineditswideuseasprognosticmodeltoevaluatesurvivalincirrho- sis. However,theChild-Pughclassicationhassomedrawbacksthatlimititsuseasprognosticclassicationforpatientswithascites.First,itdoesnotincludevari-ablesofrenalorcirculatoryfunction,whichareknowntobeveryimportantprognosticfactorsinthesepatients.Second,prothrombintimewhichisoneofthevariablesincludedintheclassicationhaslittleprognosticval

ue inpatientswithascites[5,10].Third,thescoredoesnotdistinguishpatientswithserumbilirubinvaluesof 10mg/dLor20mg/dLorhigher.Lastly,theChild-Pughclassicationincludeshepaticencephalopathyandas-cites,twomeasuresthataresubjecttoawideclinical interpretationandaremuchlessobjective.Themain problemwiththeChild-Pughclassicationisforpa-tientsthatbelongtotheChildPughclassB.ItiswellknownthatChild-PughclassApatientsusuallyshowgoodmidtermsurvivalwithouttransplantationunless othercomplicationsoccur hileChild

esfor livertransplant.However,ChildPughclassBpatients

areaheterogeneousgroupinwhichpatientscouldre-mainstableforalongperiodorontheotherhandcansuddenlydeteriorateintoclassC.Althoughthesept-fallswereknownforyears,nootherprognosticmodelofwideapplicabilityandobjectivemeasureshadbeen identied.TheMELDscorewascreatedinaimsofbetterpre-dictingsurvivalinpatientsundergoingatransjugular

intrahepaticshunt(TIPS)placement[32].Inthismod- el,INR,totalserumbilirubinlevel,serumcreatininelevel, and etiology of cirrhosis were used topredictsurvivalfollowingplacementofaTIPSforanycauseThisprognosticindexwasmodiedbyremovingtheetiology and then implemented in the UnitedStates

7/28/2019 66904554

14/22

ertransplantation[32]. Theadvantagesofthissystemarethatvariablesareobjectiveandpredic-

tive.Forinstance,bilirubinisarobustvariablealsoin- cludedintheChild-Pughclassication;renaldysfunc- tionisawell-knownvariableassociatedwith apoorprognosisin cirrhoticpatients; and INRistheinter-nationalnormalizedratioforprothrombintime.TheMELDmodelisalsopracticalforintheriskstratica-tionofpatientsundergoingTIPS,shorttermsurvivalpredictionofHRSandacutevaricealbleeding[3739] andrisk stratication for non-

transplantsurgery[40,41].MELDhasadvantagesoverChildPughbecauseitincludesvariablesrelatedtobothliverandrenalfunc-tion.Thisscorealsoexcludessubjectivevariables,like encephalopathyandascites.Nevertheless,studiesin-dicatethatsomesubsetsofpatientswithcirrhosismay have high mortality despite low MELD scores[42].Althoughpatientswithasciteswithseveresodiumre-

tentionanddilutionalhyponatremiahaveapoorprog-nosis,theymayhavealowMELDscoreiftheyhavenormalcreatininelevels.Sincehyponatremiaandim- pairedsolute-freewaterexcretionareeventsassociat-edtodevelopmentofHRSandhavebeenassociated withincreasedliver-relatedmortality[43]theaddition

ofserumsodiumtoMELDscore(MELD-Na)hasbeenproposedasbetterprognosticmodelinpatientsawait-

inglivertransplantation[44].InastudyfromtheUSAtheabilityofserumsodiumtoaddprognosticcapabl-itytotheMELDscorewasanalyzedinadultprimarylivertransplantcandidateswithcirrhosisregisteredfor transplantationduring2005and2006[45]BoththeMELDscoreandtheserumsodiumconcentrationwerepredictorsofmortalityandwhencombinedintoanew MELD

Nascore,thosepatientswithlowMELDscoresbenetedmostfromthenewscoringsystem.Although themost acceptedprognosticmodelinpatientswithcirrhosisawaitingLTinUSAandseveralothercoun-triesistheMELDscore,theChild-Pughclassstillisconsideredanimportantprognosticfactorspecicallyinthosethatarebeingconsideredforsurgeryoranother majorintervention.

8. Hepatorenalsyndrome

HRSisapre-renalrenalfailurewithoutanyidenti-ablekidneypathologythatoccursinpatientswithad-vancedcirrhosis[20].Duetothelackofspecicdiag-nosticmarkers,thediagnosisofHRSiscurrentlymadeusingcriteriatoexcludeothercausesofrenalfailure

7/28/2019 66904554

15/22

144

7/28/2019 66904554

16/22

y

n

d

r

o

m

e

i

n

c

i

r

r

h

o

s

i

s

1

.

C

i

r

r

h

o

s

i

s

w

i

t

h

as

c

i

t

e

s

2.Ser

umcr

eatin

ine

>

1.5mg/dL3.Noi

mcreatinine(decreasetoalevellowerthan1.5mg/dLafteratleasttwodaysoffdiureticsandvolumeexpansionwithalbumin(1g/kgbodyweightuptoamaximumof100g/day) 4.Absenceofshock5.Nocurrentorrecenttreatmentwithnephrotoxicdrugs

6.Absenceofsignsofparenchymalrenaldisease,assuggestedbyproteinuria( >

500mg/day)orhematuria

(

7/28/2019 66904554

17/22

thatcanoccurincirrhosis(Table3).Patientswhode-velopHRShavemoreadvancedliverdiseaseandf

ea-turesofcirculatorydysfunction,withmarkedhypoten-sion,lowsystemicvascularresistance,veryhighlevelsofreninactivity,norepinephrineandAVP.Thesepa-tientsusuallyhavelowurinevolumeandintensesodi-umretention,withurinesodium20mEq/L.Thean-nualincidenceofHRSinpatientswithascitesisap-proximately8%andoccursinabout10%ofhospit

al-izedpatientswithcirrhosisandascites.TheprobabilityofdevelopingHRSinpatientswithcirrhosisandascitesis18%atoneyearan39%atveyears[14].TherearetwotypesofHRS;inType1HRSrenalfunctiondete-rioratesrapidlywithanincreaseinserumcreatini

Predictivefactorsassociatedwithagreaterriskofde-

velopingHRShavebeendescribedincirrhoti

cpatientswithasciteswithoutrenalfailure[14,15].Patientswithintensesodiumretention(

7/28/2019 66904554

18/22

L.NazalandA.Cardenas/Prognosticmarkersinpatients withascitesandhepatorenal syndrome 145typesofHRS[39].Thescorecanbeusefulintheman-agementofpatientswithHRS,particularlyforpatie

nts whoarecandidatesforlivertransplantation.Mostpa- tientswithtype1HRShaveaMELDscore

20[39].AMELDscore >

20inpatientswithHRStype2isas-sociatedwithpooroutcomecomparedtothatofpatientswithMELD

Documents

66904554