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Cirrhosis
Author:DavidCWolf,MD,FACP,FACG,AGAF,FAASLDChiefEditor:BSAnand,MDmore...
Updated:Dec10,2014

PracticeEssentials
Cirrhosisisdefinedhistologicallyasadiffusehepaticprocesscharacterizedby
fibrosisandtheconversionofnormalliverarchitectureintostructurallyabnormal
nodules.Theprogressionofliverinjurytocirrhosismayoccuroverweekstoyears.
Essentialupdate:TURQUOISEIIdatasuggest3D+RBVimprovesliver
functioninhepatitisCpatientswithcirrhosis
AccordingtoananalysisofdatafromtheTURQUOISEIIstudy,presentedin
October2014attheAnnualScientificMeetingoftheAmericanCollegeof
Gastroenterology(ACG),treatmentwiththecombinationoftheproteaseinhibitor
ABT450boostedwithritonavir,theNS5Ainhibitorombitasvir,andthenon
nucleosidepolymeraseinhibitordasabuvirplusribavirin(3D+RBV)improved
measuresofliverfunctionat12weeksinhepatitisCpatientswithcirrhosis.[1]
Highlysignificantimprovementsfrombaselinewereseenat12weeksfortheliver
enzymesalanineaminotransferase,aspartateaminotransferase,andgamma
glutamyltransferase.[1]Amongpatientswithelevatedtransaminaselevelsat
baseline,levelsnormalizedafter12weeksin7090%ofcases.Highlysignificant
improvementswerealsoobservedinconjugatedbilirubinandalbuminlevelsandin
prothrombintimeat12weeks.

Signsandsymptoms
Somepatientswithcirrhosisarecompletelyasymptomaticandhaveareasonably
normallifeexpectancy.Otherindividualshaveamultitudeofthemostsevere
symptomsofendstageliverdiseaseandalimitedchanceforsurvival.Common
signsandsymptomsmaystemfromdecreasedhepaticsyntheticfunction(eg,
coagulopathy),portalhypertension(eg,varicealbleeding),ordecreased
detoxificationcapabilitiesoftheliver(eg,hepaticencephalopathy).
Portalhypertension
Portalhypertensioncanhaveprehepatic,intrahepatic,orposthepaticcauses.Budd
Chiarisyndrome,aposthepaticcause,ischaracterizedbythefollowingsymptoms:
Hepatomegaly
Abdominalpain
Ascites
Ascitesissuggestedbythefollowingfindingsonphysicalexamination:
Abdominaldistention
Bulgingflanks
Shiftingdullness
Elicitationofa"puddlesign"inpatientsinthekneeelbowposition
Hepaticencephalopathy
Thesymptomsofhepaticencephalopathymayrangefrommildtosevereandmay
beobservedinasmanyas70%ofpatientswithcirrhosis.Symptomsaregradedon
thefollowingscale:
Grade0Subclinicalnormalmentalstatusbutminimalchangesinmemory,
concentration,intellectualfunction,coordination
Grade1Mildconfusion,euphoriaordepression,decreasedattention,
slowingofabilitytoperformmentaltasks,irritability,disorderofsleeppattern
(ie,invertedsleepcycle)
Grade2Drowsiness,lethargy,grossdeficitsinabilitytoperformmental
tasks,obviouspersonalitychanges,inappropriatebehavior,intermittent
disorientation(usuallywithregardtotime)
Grade3Somnolent,butarousablestateinabilitytoperformmentaltasks
disorientationwithregardtotimeandplacemarkedconfusionamnesia
occasionalfitsofragespeechispresentbutincomprehensible
Grade4Coma,withorwithoutresponsetopainfulstimuli
Findingsonphysicalexaminationinhepaticencephalopathyincludeasterixisand
fetorhepaticus.
Additionalsignsandsymptoms
Manypatientswithcirrhosisexperiencefatigue,anorexia,weightloss,andmuscle
wasting.Cutaneousmanifestationsofcirrhosisincludejaundice,spiderangiomata,
skintelangiectasias("papermoneyskin"),palmarerythema,whitenails,
disappearanceoflunulae,andfingerclubbing,especiallyinthesettingof
hepatopulmonarysyndrome.

Diagnosis
Hepatorenalsyndrome
Hepatorenalsyndromeisdiagnosedwhenacreatinineclearancerateoflessthan
40mL/minispresentorwhenaserumcreatininelevelofgreaterthan1.5mg/dL,a

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urinevolumeoflessthan500mL/day,andaurinesodiumleveloflessthan10mEq/L
arepresent.[2]Urineosmolalityisgreaterthanplasmaosmolality.
Portalhypertension
Duringangiography,acathetermaybeplacedselectivelyviaeitherthetransjugular
ortransfemoralrouteintothehepaticveintomeasureportalpressure.
Hepaticencephalopathy
Anelevatedarterialorfreevenousserumammonialevelistheclassiclaboratory
abnormalityreportedinpatientswithhepaticencephalopathy.
Electroencephalographymaybehelpfulintheinitialworkupofapatientwith
cirrhosisandalteredmentalstatus,whenrulingoutseizureactivitymaybe
necessary.
Computedtomography(CT)scanningandMRIstudiesofthebrainmaybe
importantinrulingoutintracraniallesionswhenthediagnosisofhepatic
encephalopathyisinquestion.
Ascites
Paracentesisisessentialindeterminingwhetherascitesiscausedbyportal
hypertensionorbyanotherprocess.

Management
Specificmedicaltherapiesmaybeappliedtomanyliverdiseasesinaneffortto
diminishsymptomsandtopreventorforestallthedevelopmentofcirrhosis.
Examplesofsuchtreatmentsincludethefollowing:
PrednisoneandazathioprineForautoimmunehepatitis
InterferonandotherantiviralagentsForhepatitisBandC
PhlebotomyForhemochromatosis
UrsodeoxycholicacidForprimarybiliarycirrhosis
TrientineandzincForWilsondisease
Oncecirrhosisdevelops,treatmentisaimedatthemanagementofcomplicationsas
theyarise.Examplesincludethefollowing:
HepatorenalsyndromeKidneyfunctionusuallyrecoverswhenpatientswith
cirrhosisandhepatorenalsyndromeundergolivertransplantationpatients
withearlyhepatorenalsyndromemaybesalvagedbyaggressiveexpansion
ofintravascularvolumewithalbuminandfreshfrozenplasmaandby
avoidanceofdiuretics
HepaticencephalopathyPharmacologictreatmentincludesthe
administrationoflactuloseandantibiotics
AscitesTreatmentcanincludesodiumrestrictionandtheuseofdiuretics,
largevolumeparacentesis,andshunts(peritoneovenous,portosystemic,
transjugularintrahepaticportosystemic)
Livertransplantation
Patientsshouldbereferredforconsiderationforlivertransplantationafterthefirst
signsofhepaticdecompensation.

Overview
Cirrhosisrepresentsthefinalcommonhistologicpathwayforawidevarietyof
chronicliverdiseases.ThetermcirrhosiswasfirstintroducedbyLaennecin1826.It
isderivedfromtheGreektermscirrhusandreferstotheorangeortawnysurfaceof
theliverseenatautopsy.
Cirrhosisisdefinedhistologicallyasadiffusehepaticprocesscharacterizedby
fibrosisandtheconversionofnormalliverarchitectureintostructurallyabnormal
nodules.Theprogressionofliverinjurytocirrhosismayoccuroverweekstoyears.
Indeed,patientswithhepatitisCmayhavechronichepatitisforaslongas40years
beforeprogressingtocirrhosis.
Manyformsofliverinjuryaremarkedbyfibrosis,whichisdefinedasanexcess
depositionofthecomponentsoftheextracellularmatrix(ie,collagens,glycoproteins,
proteoglycans)withintheliver.Thisresponsetoliverinjurypotentiallyisreversible.
Bycontrast,inmostpatients,cirrhosisisnotareversibleprocess.
Inadditiontofibrosis,thecomplicationsofcirrhosisinclude,butarenotlimitedto,
portalhypertension,ascites,hepatorenalsyndrome,andhepaticencephalopathy.
Oftenapoorcorrelationexistsbetweenthehistologicfindingsincirrhosisandthe
clinicalpicture.Somepatientswithcirrhosisarecompletelyasymptomaticandhave
areasonablynormallifeexpectancy.Otherindividualshaveamultitudeofthemost
severesymptomsofendstageliverdiseaseandhavealimitedchanceforsurvival.
Commonsignsandsymptomsmaystemfromdecreasedhepaticsyntheticfunction
(eg,coagulopathy),decreaseddetoxificationcapabilitiesoftheliver(eg,hepatic
encephalopathy),orportalhypertension(eg,varicealbleeding).

Patienteducation
Forpatienteducationinformation,seetheMentalHealthCenter,aswellas
Alcoholism.
InAugust2012,theCentersforDiseaseControlandPrevention(CDC)expanded
theirexisting,riskbasedtestingguidelinestorecommenda1timebloodtestfor
hepatitisCvirus(HCV)infectioninbabyboomersthegenerationbornbetween
1945and1965,whoaccountforapproximatelythreefourthsofallchronicHCV
infectionsintheUnitedStateswithoutpriorascertainmentofHCVrisk(see
RecommendationsfortheIdentificationofChronicHepatitisCVirusInfectionAmong

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PersonsBornDuring19451965).[3]OnetimeHCVtestinginthispopulationcould
identifynearly808,600additionalpeoplewithchronicinfection.Allindividuals
identifiedwithHCVshouldbescreenedand/ormanagedforalcoholabuse,followed
byreferraltopreventativeand/ortreatmentservices,asappropriate.

Epidemiology
Chronicliverdiseaseandcirrhosisresultinabout35,000deathseachyearinthe
UnitedStates.CirrhosisistheninthleadingcauseofdeathintheUnitedStatesand
isresponsiblefor1.2%ofallUSdeaths.Manypatientsdiefromthediseaseintheir
fifthorsixthdecadeoflife.
Eachyear,2000additionaldeathsareattributedtofulminanthepaticfailure(FHF).
FHFmaybecausedviralhepatitis(eg,hepatitisAandB),drugs(eg,
acetaminophen),toxins(eg,Amanitaphalloides,theyellowdeathcapmushroom),
autoimmunehepatitis,Wilsondisease,oravarietyoflesscommonetiologies.
Cryptogeniccausesareresponsibleforonethirdoffulminantcases.Patientswith
thesyndromeofFHFhavea5080%mortalityrateunlesstheyaresalvagedbyliver
transplantation.

Etiology
Alcoholicliverdiseaseoncewasconsideredtobethepredominantsourceof
cirrhosisintheUnitedStates,buthepatitisChasemergedasthenation'sleading
causeofchronichepatitisandcirrhosis.
Manycasesofcryptogeniccirrhosisappeartohaveresultedfromnonalcoholicfatty
liverdisease(NAFLD).Whencasesofcryptogeniccirrhosisarereviewed,many
patientshave1ormoreoftheclassicriskfactorsforNAFLD:obesity,diabetes,and
hypertriglyceridemia.[4]Itispostulatedthatsteatosismayregressinsomepatients
ashepaticfibrosisprogresses,makingthehistologicdiagnosisofNAFLDdifficult.
UptoonethirdofAmericanshaveNAFLD.About23%ofAmericanshave
nonalcoholicsteatohepatitis(NASH),inwhichfatdepositioninthehepatocyteis
complicatedbyliverinflammationandfibrosis.Itisestimatedthat10%ofpatients
withNASHwillultimatelydevelopcirrhosis.NAFLDandNASHareanticipatedto
haveamajorimpactontheUnitedStates'publichealthinfrastructure.

MostcommoncausesofcirrhosisintheUnitedStates
Seethelistbelow:
HepatitisC(26%)
Alcoholicliverdisease(21%)
HepatitisCplusalcoholicliverdisease(15%)
Cryptogeniccauses(18%)ManycasesactuallyareduetoNAFLD
HepatitisBMaybecoincidentwithhepatitisD(15%)
Miscellaneous(5%)

Miscellaneouscausesofchronicliverdiseaseandcirrhosis
Seethelistbelow:
Autoimmunehepatitis
Primarybiliarycirrhosis
SecondarybiliarycirrhosisAssociatedwithchronicextrahepaticbileduct
obstruction
Primarysclerosingcholangitis
Hemochromatosis
Wilsondisease
Alpha1antitrypsindeficiency
GranulomatousdiseaseEg,sarcoidosis
TypeIVglycogenstoragedisease
DruginducedliverdiseaseEg,methotrexate,alphamethyldopa,
amiodarone
VenousoutflowobstructionEg,BuddChiarisyndrome,venoocclusive
disease
Chronicrightsidedheartfailure
Tricuspidregurgitation

HepaticFibrosis
Thedevelopmentofhepaticfibrosisreflectsanalterationinthenormallybalanced
processesofextracellularmatrixproductionanddegradation.[5]Theextracellular
matrix,thenormalscaffoldingforhepatocytes,iscomposedofcollagens(especially
typesI,III,andV),glycoproteins,andproteoglycans.
Stellatecells,locatedintheperisinusoidalspace,areessentialfortheproductionof
extracellularmatrix.Stellatecells,whichwereonceknownasItocells,lipocytes,or
perisinusoidalcells,maybecomeactivatedintocollagenformingcellsbyavarietyof
paracrinefactors.Suchfactorsmaybereleasedbyhepatocytes,Kupffercells,and
sinusoidalendotheliumfollowingliverinjury.Asanexample,increasedlevelsofthe
cytokinetransforminggrowthfactorbeta1(TGFbeta1)areobservedinpatientswith
chronichepatitisCandthosewithcirrhosis.TGFbeta1,inturn,stimulatesactivated
stellatecellstoproducetypeIcollagen.
IncreasedcollagendepositioninthespaceofDisse(thespacebetween
hepatocytesandsinusoids)andthediminutionofthesizeofendothelialfenestrae
leadtothecapillarizationofsinusoids.Activatedstellatecellsalsohavecontractile
properties.Capillarizationandconstrictionofsinusoidsbystellatecellscontributeto
thedevelopmentofportalhypertension.
Futuredrugstrategiestopreventfibrosismayfocusonreducinghepatic
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stellatecells,andstimulatingmatrixdegradation.

PortalHypertension
Causes
Thenormalliverhastheabilitytoaccommodatelargechangesinportalbloodflow
withoutappreciablealterationsinportalpressure.Portalhypertensionresultsfroma
combinationofincreasedportalvenousinflowandincreasedresistancetoportal
bloodflow.
Patientswithcirrhosisdemonstrateincreasedsplanchnicarterialflowand,
accordingly,increasedsplanchnicvenousinflowintotheliver.Increasedsplanchnic
arterialflowisexplainedpartlybydecreasedperipheralvascularresistanceand
increasedcardiacoutputinthepatientwithcirrhosis.Nitricoxideappearstobethe
majordrivingforceforthisphenomenon.[6]
Furthermore,evidenceforsplanchnicvasodilationexists.Putativesplanchnic
vasodilatorsincludeglucagon,vasoactiveintestinalpeptide,substanceP,
prostacyclin,bileacids,tumornecrosisfactoralpha(TNFalpha),andnitricoxide.
Increasedresistanceacrossthesinusoidalvascularbedoftheliveriscausedby
fixedfactorsanddynamicfactors.Twothirdsofintrahepaticvascularresistancecan
beexplainedbyfixedchangesinthehepaticarchitecture.Suchchangesincludethe
formationofregeneratingnodulesand,aftertheproductionofcollagenbyactivated
stellatecells,depositionofthecollagenwithinthespaceofDisse.
Dynamicfactorsaccountforonethirdofintrahepaticvascularresistance.Stellate
cellsserveascontractilecellsforadjacenthepaticendothelialcells.Thenitricoxide
producedbytheendothelialcells,inturn,controlstherelativedegreeofvasodilation
orvasoconstrictionproducedbythestellatecells.Incirrhosis,decreasedlocal
productionofnitricoxidebyendothelialcellspermitsstellatecellcontraction,with
resultingvasoconstrictionofthehepaticsinusoid.(Thiscontrastswiththeperipheral
circulation,wheretherearehighcirculatinglevelsofnitricoxideincirrhosis.)
Increasedlocallevelsofvasoconstrictingchemicals,suchasendothelin,mayalso
contributetosinusoidalvasoconstriction.
Theportalhypertensionofcirrhosisiscausedbythedisruptionofhepaticsinusoids.
However,portalhypertensionmaybeobservedinavarietyofnoncirrhotic
conditions.
Prehepaticcauses
Prehepaticcausesincludesplenicveinthrombosisandportalveinthrombosis.
Theseconditionscommonlyareassociatedwithhypercoagulablestatesandwith
malignancy(eg,pancreaticcancer).
Intrahepaticcauses
Intrahepaticcausesofportalhypertensionaredividedintopresinusoidal,sinusoidal,
andpostsinusoidalconditions.Theclassicsinusoidalcauseofportalhypertensionis
cirrhosis.
Theclassicformofpresinusoidalportalhypertensioniscausedbythedepositionof
Schistosomaoocytesinpresinusoidalportalvenules,withthesubsequent
developmentofgranulomataandportalfibrosis.Schistosomiasisisthemost
commonnoncirrhoticcauseofvaricealbleedingworldwide.Schistosomamansoni
infectionisdescribedinPuertoRico,CentralandSouthAmerica,theMiddleEast,
andAfrica.SjaponicumisdescribedintheFarEast.Shematobium,observedinthe
MiddleEastandAfrica,canproduceportalfibrosisbutmorecommonlyisassociated
withurinarytractdepositionofeggs.
Theclassicpostsinusoidalconditionisanentityknownasvenoocclusivedisease.
Obliterationoftheterminalhepaticvenulesmayresultfromingestionofpyrrolizidine
alkaloidsinComfreyteaorJamaicanbushteaorfollowingthehighdose
chemotherapythatprecedesbonemarrowtransplantation.
Posthepaticcauses
Posthepaticcausesofportalhypertensionmayincludechronicrightsidedheart
failureandtricuspidregurgitationandobstructinglesionsofthehepaticveinsand
inferiorvenacava.Thelatterconditions,andthesymptomstheyproduce,are
termedBuddChiarisyndrome.Predisposingconditionsincludehypercoagulable
states,tumorinvasionintothehepaticveinorinferiorvenacava,andmembranous
obstructionoftheinferiorvenacava.Inferiorvenacavawebsareobservedmost
commonlyinSouthandEastAsiaandarepostulatedtobeduetonutritionalfactors.
SymptomsofBuddChiarisyndromeareattributedtodecreasedoutflowofblood
fromtheliver,withresultinghepaticcongestionandportalhypertension.These
symptomsincludehepatomegaly,abdominalpain,andascites.Cirrhosisensues
onlylaterinthecourseofdisease.DifferentiatingBuddChiarisyndromefrom
cirrhosisbyhistoryorphysicalexaminationmaybedifficult.Thus,BuddChiari
syndromemustbeincludedinthedifferentialdiagnosisofconditionsthatproduce
ascitesandvarices.
Hepaticveinpatencyischeckedmostreadilybyperformingabdominal
ultrasonography,withDopplerexaminationofthehepaticvessels.Abdominal
computedtomography(CT)scanningwithintravenous(IV)contrast,abdominal
magneticresonanceimaging(MRI),andvisceralangiographyalsomayprovide
informationregardingthepatencyofhepaticvessels.

Measurement
Widespreaduseofthetransjugularintrahepaticportosystemicshunt(TIPS)
procedureinthe1990sforthemanagementofvaricealbleedingledtoaresurgence
ofclinicians'interestinmeasuringportalpressure.Duringangiography,acatheter
maybeplacedselectivelyviaeitherthetransjugularortransfemoralrouteintothe

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hepaticvein.Inthehealthypatient,freehepaticveinpressure(FHVP)isequalto
inferiorvenacavapressure.FHVPisusedasaninternalzeroreferencepoint.
Wedgedhepaticvenouspressure(WHVP)ismeasuredbyinflatingaballoonatthe
cathetertip,thusoccludingahepaticveinbranch.MeasurementoftheWHVP
providesacloseapproximationofportalpressure.TheWHVPactuallyisslightly
lowerthantheportalpressurebecauseofsomedissipationofpressureinthe
sinusoidalbed.TheWHVPandportalpressureareelevatedinpatientswith
sinusoidalportalhypertension,asisobservedincirrhosis.

Complications
Thehepaticvenouspressuregradient(HVPG)isdefinedasthedifferencein
pressurebetweentheportalveinandtheinferiorvenacava.Thus,theHVPGis
equaltotheWHVPvalueminustheFHVPvalue(ie,HVPG=WHVPFHVP).The
normalHVPGis36mmHg.
Portalhypertensionisdefinedasasustainedelevationofportalpressureabove
normal.AnHVPGof8mmHgisbelievedtobethethresholdabovewhichascites
potentiallycandevelop.AnHVPGof12mmHgisthethresholdforthepotential
formationofvarices.Highportalpressuresmaypredisposepatientstoanincreased
riskofvaricealhemorrhage.[7]

Ascites
Ascites,whichisanaccumulationofexcessivefluidwithintheperitonealcavity,can
beacomplicationofeitherhepaticornonhepaticdisease.The4mostcommon
causesofascitesinNorthAmericaandEuropearecirrhosis,neoplasm,congestive
heartfailure,andtuberculousperitonitis.
Inthepast,asciteswasclassifiedasbeingatransudateoranexudate.In
transudativeascites,fluidwassaidtocrossthelivercapsulebecauseofan
imbalanceinStarlingforces.Ingeneral,ascitesproteinwouldbelessthan2.5g/dL
inthisformofascites.Aclassiccauseoftransudativeasciteswouldbeportal
hypertensionsecondarytocirrhosisandcongestiveheartfailure.
Inexudativeascites,fluidwassaidtoweepfromaninflamedortumorladen
peritoneum.Ingeneral,ascitesproteininexudativeasciteswouldbegreaterthan
2.5g/dL.Causesoftheconditionwouldincludeperitonealcarcinomatosisand
tuberculousperitonitis.

Nonperitonealcauses
Attributingascitestodiseasesofnonperitonealorperitonealoriginismoreuseful.
ThankstotheworkofBruceRunyon,theserumascitesalbumingradient(SAAG)
hascomeintocommonclinicalusefordifferentiatingtheseconditions.
NonperitonealdiseasesproduceasciteswithaSAAGgreaterthan1.1g/dL.(See
Table1,below.)[8]
Table1.NonperitonealCausesofAscites[9](OpenTableinanewwindow)
CausesofNonperitoneal
Ascites

Examples
Cirrhosis

Fulminanthepaticfailure
Intrahepaticportalhypertension
Venoocclusivedisease

Hepaticveinobstruction(ie,BuddChiari
syndrome)
Extrahepaticportalhypertension
Congestiveheartfailure

Nephroticsyndrome

Hypoalbuminemia

ProteinlosingenteropathyMalnutrition

Myxedema

Ovariantumors

Miscellaneousdisorders

Pancreaticascites

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Biliaryascites

Secondarytomalignancy

Secondarytotrauma
Chylous
Secondarytoportalhypertension

Chylousascites,causedbyobstructionofthethoracicductorcisternachyli,most
oftenisduetomalignancy(eg,lymphoma)butoccasionallyisobserved
postoperativelyandfollowingradiationinjury.Chylousascitesalsomaybeobserved
inthesettingofcirrhosis.Thetriglycerideconcentrationoftheascitesisgreaterthan
110mg/dLandgreaterthanthatobservedinplasma.Patientsshouldbeplacedona
lowfatdietthatissupplementedwithmediumchaintriglycerides.Treatmentwith
diureticsandlargevolumeparacentesismayberequired.

Peritonealcauses
PeritonealdiseasesproduceasciteswithaSAAGoflessthan1.1g/dL.(SeeTable
2,below.)
Table2.PeritonealCausesofAscites[9](OpenTableinanewwindow)
Causesof
PeritonealAscites

Examples
Primaryperitonealmesothelioma

Malignantascites

Secondaryperitonealcarcinomatosis

Tuberculousperitonitis

Fungalandparasiticinfections(eg,Candida,

Histoplasma,Cryptococcus,Schistosomamansoni,
Strongyloides,Entamoebahistolytica)
Granulomatous
peritonitis

Sarcoidosis

Foreignbodies(ie,talc,cottonandwoodfibers,

starch,barium)

Systemiclupuserythematosus

Vasculitis

HenochSchnleinpurpura

Eosinophilicgastroenteritis

Whippledisease
Miscellaneous
disorders
Endometriosis

Theroleofportalhypertensioninthepathogenesisofcirrhotic
ascites
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Theformationofascitesincirrhosisdependsonthepresenceofunfavorable
Starlingforceswithinthehepaticsinusoidandonsomedegreeofrenaldysfunction.
Patientswithcirrhosisareobservedtohaveincreasedhepaticlymphaticflow.
Fluidandplasmaproteinsdiffusefreelyacrossthehighlypermeablesinusoidal
endotheliumintothespaceofDisse.FluidinthespaceofDisse,inturn,entersthe
lymphaticchannelsthatrunwithintheportalandcentralvenousareasoftheliver.
Becausethetranssinusoidaloncoticgradientisapproximatelyzero,theincreased
sinusoidalpressurethatdevelopsinportalhypertensionincreasestheamountof
fluidenteringthespaceofDisse.Whentheincreasedhepaticlymphproduction
observedinportalhypertensionexceedstheabilityofthecisternachyliandthoracic
ducttoclearthelymph,fluidcrossesintotheliverinterstitium.Fluidmaythen
extravasateacrossthelivercapsuleintotheperitonealcavity.

Theroleofrenaldysfunctioninthepathogenesisofcirrhotic
ascites
Patientswithcirrhosisexperiencesodiumretention,impairedfreewaterexcretion,
andintravascularvolumeoverload.Theseabnormalitiesmayoccureveninthe
settingofanormalglomerularfiltrationrate.Theyare,tosomeextent,dueto
increasedlevelsofreninandaldosterone.
Theperipheralarterialvasodilationhypothesisstatesthatsplanchnicarterial
vasodilation,drivenbyhighnitricoxidelevels,leadstointravascularunderfilling.
Thiscausesstimulationofthereninangiotensinsystemandthesympathetic
nervoussystemandalsoresultsinantidiuretichormonerelease.Theseeventsare
followedbyanincreaseinsodiumandwaterretentionandinplasmavolume,as
wellasbytheoverflowofascitesintotheperitonealcavity.

Clinicalfeaturesofascites
Ascitesissuggestedbythepresenceofthefollowingfindingsuponphysical
examination:
Abdominaldistention
Bulgingflanks
Shiftingdullness
Elicitationofa"puddlesign"inpatientsinthekneeelbowposition
Afluidwavemaybeelicitedinpatientswithmassivetenseascites.However,
physicalexaminationfindingsaremuchlesssensitivethanabdominal
ultrasonography,whichcandetectaslittleas30mLoffluid.Furthermore,
ultrasonographywithDopplercanhelptoassessthepatencyofhepaticvessels.
Factorsassociatedwithworseningofascitesincludeexcessfluidorsaltintake,
malignancy,venousocclusion(eg,BuddChiarisyndrome),progressiveliver
disease,andspontaneousbacterialperitonitis(SBP).

Spontaneousbacterialperitonitis
SBPisobservedin1526%ofpatientshospitalizedwithascites.Thesyndrome
arisesmostcommonlyinpatientswhoselowproteinascites(<1g/dL)containslow
levelsofcomplement,resultingindecreasedopsonicactivity.SBPappearstobe
causedbythetranslocationofgastrointestinal(GI)tractbacteriaacrossthegutwall
andalsobythehematogenousspreadofbacteria.Themostcommoncausative
organismsareEscherichiacoli,Streptococcuspneumoniae,Klebsiellaspecies,and
othergramnegativeentericorganisms.[10]
ClassicSBPisdiagnosedbythepresenceofneutrocytosis,whichisdefinedas
greaterthan250polymorphonuclearcells(PMNs)permm3ofascites,inthesetting
ofapositiveascitesculture.Culturenegativeneutrocyticascitesisobservedmore
commonly.Bothconditionsrepresentseriousinfectionsthatcarrya2030%
mortalityrate.
ThemostcommonlyusedregimeninthetreatmentofSBPisa5daycourseof
cefotaximeat12gintravenouslyevery8hours.[11]Alternativesincludeoralofloxacin
andotherIVantibioticswithactivityagainstgramnegativeentericorganisms.Many
authoritiesadviserepeatparacentesisin4872hourstodocumentadecreaseinthe
ascitesPMNcounttolessthan250cells/mm3andtoensuretheefficacyoftherapy.
OnceSBPdevelops,patientshavea70%chanceofredevelopingthecondition
within1year.ProphylacticantibiotictherapycanreducetherecurrencerateofSBP
to20%.SomeoftheregimensusedintheprophylaxisofSBPincludenorfloxacinat
400mgorallyeveryday[12]andtrimethoprimsulfamethoxazoleat1doublestrength
tablet5daysperweek.[13]
Therapywithnorfloxacinat400mgorallytwiceperdayfor7dayscanreduce
seriousbacterialinfectioninpatientswithcirrhosiswhohaveGIbleeding.Onestudy
notedthatthe37%incidenceofseriousbacterialinfectionwasreducedto10%
whentreatmentwithnorfloxacinwasinstituted.[14]Furthermore,itcanbearguedthat
allpatientswithlowproteinascitesshouldundergoprophylactictherapy(eg,with
norfloxacin400mgdailyPO)atthetimeofhospitaladmission,giventhehigh
incidenceofhospitalacquiredSBP.[15]

Hernias
Umbilicalandinguinalherniasarecommoninpatientswithmoderateandmassive
ascites.Theuseofanelasticabdominalbindermayprotecttheskinoverlyinga
protrudingumbilicalherniafrommacerationandmayhelptopreventruptureand
subsequentinfection.Timely,largevolumeparacentesisalsomayhelptoprevent
thisdisastrouscomplication.
Umbilicalherniasshouldnotundergoelectiverepairunlesspatientsaresignificantly
symptomaticortheirherniasareirreducible.Aswithallothersurgeriesinpatients

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withcirrhosis,herniorrhaphycarriesmultiplepotentialrisks,suchasintraoperative
bleeding,postoperativeinfection,andliverfailure,becauseofanesthesiainduced
reductionsinhepaticbloodflow.However,theserisksbecomeacceptablein
patientswithseveresymptomsfromtheirhernia.Urgentsurgeryisnecessaryinthe
patientwhoseherniahasbeencomplicatedbybowelincarceration.

Othercomplicationsofmassiveascites
Patientswithmassiveascitesmayexperienceabdominaldiscomfort,depressed
appetite,anddecreasedoralintake.Diaphragmaticelevationmayleadtosymptoms
ofdyspnea.Pleuraleffusionsmayresultfromthepassageofasciticfluidacross
channelsinthediaphragm.

Paracentesisinthediagnosisofascites
Paracentesisisessentialindeterminingwhetherascitesiscausedbyportal
hypertensionorbyanotherprocess.Ascitesstudiesalsoareusedtoruleout
infectionandmalignancy.Paracentesisshouldbeperformedinallpatientswith
eithernewonsetofascitesorworseningascites.Paracentesisalsoshouldbe
performedwhenSBPissuggestedbythepresenceofabdominalpain,fever,
leukocytosis,orworseninghepaticencephalopathy.Somearguethatparacentesis
shouldbeperformedinallpatientswithcirrhosiswhohaveascitesatthetimeof
hospitalization,giventhesignificantpossibilityofasymptomaticSBP.(SeeTable3,
below.)
Table3.AscitesTests(OpenTableinanewwindow)
Routine Optional

Special

Cell
count

Glucose(minimal
Cytology
use)

Albumin

Lactate
dehydrogenase

Tuberculosissmearandculture

Culture

Gramstain

Triglycerides(toruleoutchylousascites)

Total
protein

Bilirubin(toruleoutbiliaryleakwhenclinically
suspected)

Amylase(toruleoutpancreaticductleakwhen
clinicallysuspected)

Asciticfluidwithmorethan250PMNs/mm3definesneutrocyticascitesandSBP.
Manycasesofascitesfluidwithmorethan1000PMNs/mm3(andcertainly>5000
PMNs/mm3)areassociatedwithappendicitisoraperforatedviscuswithresulting
bacterialperitonitis.Appropriateradiologicstudiesmustbeperformedinsuch
patientstoruleoutsurgicalcausesofperitonitis.
Lymphocytepredominantascitesraisesconcernsaboutthepossibilityofunderlying
malignancyortuberculosis.Similarly,grosslybloodyascitesmaybeobservedin
malignancyandtuberculosis.(Bloodyascitesisseeninfrequentlyinuncomplicated
cirrhosis.)AcommonclinicaldilemmaishowtointerprettheascitesPMNcountin
thesettingofbloodyascites.Thisauthorrecommendssubtractionof1PMNfor
every250redbloodcells(RBCs)inascitestoascertainacorrectedPMNcount.
Theyieldofascitesculturestudiesmaybeincreasedbydirectlyinoculating10mLof
ascitesintoaerobicandanaerobicculturebottlesatthepatient'sbedside.[16]

Medicaltreatmentofascites
Therapyforascitesshouldbetailoredtothepatient'sneeds.Somepatientswith
mildascitesrespondtosodiumrestrictionordiureticstakenonceortwiceperweek.
Otherpatientsrequireaggressivediuretictherapy,carefulmonitoringofelectrolytes,
andoccasionalhospitalizationtofacilitateevenmoreintensivediuresis.
Thedevelopmentofmassiveascitesthatisrefractorytomedicaltherapyhasdire
prognosticimplications,withonly50%ofpatientssurviving6months.[17]

Sodiumrestriction
Saltrestrictionisthefirstlineoftherapy.Ingeneral,patientsbeginwithadiet
containinglessthan2000mgofsodiumdaily.Somepatientswithrefractoryascites
requireadietcontaininglessthan500mgofsodiumdaily.However,ensuringthat
patientsdonotconstructdietsthatmightplacethematriskforcalorieandprotein
malnutritionisimportant.Indeed,thebenefitofcommerciallyavailableliquid
nutritionalsupplements(whichoftencontainmoderateamountsofsodium)often
exceedstheriskofslightlyincreasingthepatient'ssaltintake.

Diuretics
Diureticsshouldbeconsideredthesecondlineoftherapy.Spironolactone
(Aldactone)blocksthealdosteronereceptoratthedistaltubule.Itisdosedat50
300mgoncedaily.Althoughthedrughasarelativelyshorthalflife,itsblockadeof
thealdosteronereceptorlastsforatleast24hours.Adverseeffectsof
spironolactoneincludehyperkalemia,gynecomastia,andlactation.Otherpotassium
sparingdiuretics,includingamilorideandtriamterene,maybeusedasalternative
agents,especiallyinpatientscomplainingofgynecomastia.
Furosemide(Lasix)maybeusedasasoloagentorincombinationwith
spironolactone.ThedrugblockssodiumreuptakeintheloopofHenle.Itisdosedat
40240mgdailyin12divideddoses.Patientsinfrequentlyneedpotassiumrepletion
whenfurosemideisdosedincombinationwithspironolactone.AnItalianstudyby
Angelietalfoundsequentialdosingwithapotassiumsparingdiureticplus
furosemidetobesuperiorforpatientswithmoderateasciteswithoutrenalfailure

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whencomparedwithpotassiumsparingdiureticmonotherapy.[18]
Aggressivediuretictherapyinhospitalizedpatientswithmassiveascitescansafely
induceaweightlossof0.51kgdaily,providedthatpatientsundergocareful
monitoringofrenalfunction.Diuretictherapyshouldbeheldintheeventof
electrolytedisturbances,azotemia,orinductionofhepaticencephalopathy.
Albumin
Thusfar,evidencebasedmedicinehasnotfirmlysupportedtheuseofalbuminas
anaidtodiuresisinapatientwithcirrhosiswhoishospitalized.Theauthor's
anecdotalexperiencesuggeststhatalbuminmayincreasetheefficacyandsafetyof
diuretics.Theauthor'spracticeinhospitalizedpatientswhoarehypoalbuminemicis
toadministerIVfurosemidefollowingIVinfusionofalbuminat25gtwicedaily,in
additiontoprovidingongoingtherapywithspironolactone.Onearticlesupportedthe
useofchronicalbumininfusionstoachievediuresisinpatientswithdiureticresistant
ascites.[19]
Albumininfusionmayprotectagainstthedevelopmentofrenalinsufficiencyin
patientswithSBP.Patientsreceivingcefotaximeandalbuminat1g/kgdaily
experiencedalowerriskofrenalfailureandalowerinhospitalmortalityratethan
patientstreatedwithcefotaximeandconventionalfluidmanagement.[20]
V2receptorantagonists
VasopressinV2receptorantagonistsareaclassofagentswiththepotentialto
increasefreewaterexcretion,improvediuresis,anddecreasetheneedfor
paracentesis.However,nosuchagenthasreceivedUSFoodandDrug
Administration(FDA)approvalforthisindication.
Tolvaptan(Samsca,OtsukaPharmaceuticalCoTokyo,Japan)isanoralV2
receptorantagonistitreceivedFDAapprovalin2009onlyforthemanagementof
hyponatremia.Ablackboxwarningcautionsagainsttreatmentinitiationin
outpatients.Furthermore,itmaybeassociatedwithanincreasedincidenceofGI
bleedinginpatientswithcirrhosis.Theauthoradvisesagainstitsuseforascites
managementatthistime.

Largevolumeparacentesis
Aggressivediuretictherapyisineffectiveincontrollingascitesinapproximately5
10%ofpatients.Suchpatientswithmassiveascitesmayneedtoundergolarge
volumeparacentesistoobtainrelieffromsymptomsofabdominaldiscomfort,
anorexia,ordyspnea.Theprocedurealsomayhelptoreducetheriskofumbilical
herniarupture.
Largevolumeparacentesiswasfirstusedinancienttimes.Itfelloutoffavorfrom
the1950sthroughthe1980swiththeadventofdiuretictherapyandfollowinga
handfulofcasereportsdescribingparacentesisinducedazotemia.In1987,Gines
andcolleaguesdemonstratedthatlargevolumeparacentesiscouldbeperformed
withminimalornoimpactonrenalfunction.[21]Thisandotherstudiesshowedthat
515Lofascitescouldberemovedsafelyatonetime.
Largevolumeparacentesisisthoughttobesafeinpatientswithperipheraledema
andinpatientsnotcurrentlytreatedwithdiuretics.Debateexistswhethercolloid
infusions(eg,with510gofalbuminper1Lofascitesremoved)arenecessaryto
preventintravascularvolumedepletioninpatientswhoarereceivingongoingdiuretic
therapyorinpatientswithmildormoderate,underlyingrenalinsufficiency.

Peritoneovenousshunts
LeVeenshuntsandDenvershuntsaredevicesthatpermitthereturnofascitesfluid
andproteinstotheintravascularspace.Plastictubinginsertedsubcutaneously
underlocalanesthesiaconnectstheperitonealcavitytotheinternaljugularveinor
subclavianveinviaapumpingchamber.Thesedevicesaresuccessfulatrelieving
ascitesandreversingproteinlossinsomepatients.However,shuntsmayclotand
requirereplacementin30%ofpatients.
Seriouscomplicationsareobservedinatleast10%oftherecipientsofthese
devices,includingperitonealinfection,sepsis,disseminatedintravascular
coagulation,congestiveheartfailure,anddeath.Theauthorconsiders
peritoneovenousshuntstobealastresortforpatientswithrefractoryasciteswho
arenotcandidatesforTIPSorlivertransplantation.Thesafetyofrepeatlarge
volumeparacentesisproceduresmayactuallyoutweighthesafetyof
peritoneovenousshuntplacement.

Portosystemicshuntsandtransjugularintrahepaticportosystemic
shunts
Theprimeindicationforportocavalshuntsurgeryisthemanagementofrefractory
varicealbleeding.Since1945,however,themedicalfieldhasrecognizedthat
portocavalshunts,bydecompressingthehepaticsinusoid,mayimproveascites.
Theperformanceofasidetosideportocavalshuntforascitesmanagementmustbe
weighedagainsttheapproximate5%mortalityrateassociatedwiththissurgeryand
thechance(ashighas30%)ofinducinghepaticencephalopathy.
ATIPSisaneffectivetoolinmanagingmassiveascitesinsomepatients.Ideally,
TIPSplacementproducesadecreaseinsinusoidalpressureandinplasmarenin
andaldosteronelevels,withsubsequentimprovedurinarysodiumexcretion.Inone
study,74%ofpatientswithrefractoryascitesachievedcompleteremissionofascites
within3monthsofTIPSplacement.[22]Typically,aboutonehalfofappropriately
selectedpatientsundergoingTIPSachievesignificantreliefofascites.
MultiplestudieshavedemonstratedthataTIPSissuperiortolargevolume
paracentesiswhenitcomestothecontrolofascites.[23]Onemetaanalysisof
individualpatientdatademonstratedanimprovementintransplantfreelife
expectancyinpatientswhosemassiveasciteswastreatedwithaTIPS,asopposed

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tolargevolumeparacentesis.[24]However,thecreationofaTIPShasthepotential
toworsenpreexistinghepaticencephalopathyandexacerbateliverdysfunctionin
patientswithsevere,underlyingliverfailure.[25]
BothapreTIPSbilirubinlevelofgreaterthan3mg/dLandapreTIPSModelfor
EndStageLiverDisease(MELD)scoreofgreaterthan18(seetheMELDScore
calculator)areassociatedwithanincreasedmortalityratewhenaTIPSiscreated
forthemanagementofascites.[26,27]Intheauthor'sopinion,TIPSuseshouldbe
reservedforpatientswithChildClassBcirrhosisorpatientswithChildClassC
cirrhosiswithoutseverecoagulopathyorencephalopathy.
Inthe1990s,shuntstenosiswasobservedinonehalfofcaseswithin1yearofTIPS
placement,necessitatingangiographicrevision.Althoughtheadventofcoated
stentsappearstohavereducedtheincidenceofshuntstenosis,patientsmuststill
bewillingtoreturntothehospitalforDopplerandangiographicfollowupofTIPS
patency.

Livertransplantation
Patientswithmassiveasciteshave1yearsurvivalrateoflessthan50%.Liver
transplantationshouldbeconsideredasapotentialmeansofsalvagingthepatient
priortotheonsetofintractableliverfailureorhepatorenalsyndrome.

HepatorenalSyndrome
Thissyndromerepresentsacontinuumofrenaldysfunctionthatmaybeobservedin
patientswithacombinationofcirrhosisandascites.Hepatorenalsyndromeis
causedbythevasoconstrictionoflargeandsmallrenalarteriesandtheimpaired
renalperfusionthatresults.[28]
Thesyndromemayrepresentanimbalancebetweenrenalvasoconstrictorsand
vasodilators.Plasmalevelsofanumberofvasoconstrictingsubstancesincluding
angiotensin,antidiuretichormone,andnorepinephrineareelevatedinpatientswith
cirrhosis.Renalperfusionappearstobeprotectedbyvasodilators,including
prostaglandinsE2andI2andatrialnatriureticfactor.
Nonsteroidalantiinflammatorydrugs(NSAIDs)inhibitprostaglandinsynthesis.They
maypotentiaterenalvasoconstriction,witharesultingdropinglomerularfiltration.
Thus,theuseofNSAIDsiscontraindicatedinpatientswithdecompensated
cirrhosis.
Mostpatientswithhepatorenalsyndromearenotedtohaveminimalhistologic
changesinthekidneys.Kidneyfunctionusuallyrecoverswhenpatientswith
cirrhosisandhepatorenalsyndromeundergolivertransplantation.Infact,akidney
donatedbyapatientdyingfromhepatorenalsyndromefunctionsnormallywhen
transplantedintoarenaltransplantrecipient.

Typesofhepatorenalsyndrome
Hepatorenalsyndromeprogressionmaybeslow(typeII)orrapid(typeI).[29]TypeI
diseasefrequentlyisaccompaniedbyrapidlyprogressiveliverfailure.Hemodialysis
offerstemporarysupportforsuchpatients.Theseindividualsaresalvagedonlyby
performanceoflivertransplantation.Exceptionstothisrulearethepatientswith
fulminanthepaticfailure(FHF)orseverealcoholichepatitiswhospontaneously
recoverliverandkidneyfunction.IntypeIIhepatorenalsyndrome,patientsmay
havestableorslowlyprogressiverenalinsufficiency.Manysuchpatientsdevelop
ascitesthatisresistanttomanagementwithdiuretics.

Diagnosis
Hepatorenalsyndromeisdiagnosedwhenacreatinineclearancerateoflessthan
40mL/minispresentorwhenaserumcreatininelevelofgreaterthan1.5mg/dL,a
urinevolumeoflessthan500mL/day,andaurinesodiumleveloflessthan10mEq/L
arepresent.[2]Urineosmolalityisgreaterthanplasmaosmolality.
Inhepatorenalsyndrome,renaldysfunctioncannotbeexplainedbypreexisting
kidneydisease,prerenalazotemia,theuseofdiuretics,orexposuretonephrotoxins.
Clinically,thediagnosismaybereachedifcentralvenouspressureisdeterminedto
benormalorifnoimprovementinrenalfunctionoccursfollowingtheinfusionofat
least1.5Lofaplasmaexpander.

Treatment
Nephrotoxicmedications,includingaminoglycosideantibiotics,shouldbeavoidedin
patientswithcirrhosis.Patientswithearlyhepatorenalsyndromemaybesalvaged
byaggressiveexpansionofintravascularvolumewithalbuminandfreshfrozen
plasmaandbyavoidanceofdiuretics.Theuseofrenaldosedopamineisnot
effective.
Anumberofinvestigatorshaveemployedsystemicvasoconstrictorsinanattemptto
reversetheeffectsofnitricoxideonperipheralarterialvasodilation.InEurope,
administrationofIVterlipressin(ananalogofvasopressinnotavailableintheUnited
States)improvedrenaldysfunctioninpatientswithhepatorenalsyndrome.[30,31]
Acombinationofmidodrine(anoralalphaagonist),subcutaneousoctreotide,and
albumininfusionhasalsobeendemonstratedtoimproverenalfunctioninsmall
cohortsofpatientswithhepatorenalsyndrome.[32]

HepaticEncephalopathy
Hepaticencephalopathy,asyndromeobservedinsomepatientswithcirrhosis,is
markedbypersonalitychanges,intellectualimpairment,andadepressedlevelof
consciousness.Thediversionofportalbloodintothesystemiccirculationappearsto

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beaprerequisiteforthesyndrome.Indeed,hepaticencephalopathymaydevelopin
patientswithoutcirrhosiswhoundergoportocavalshuntsurgery.

Pathogenesis
Anumberoftheorieshavebeenpostulatedtoexplainthepathogenesisofhepatic
encephalopathyinpatientswithcirrhosis.Patientsmayhavealteredbrainenergy
metabolismandincreasedpermeabilityofthebloodbrainbarrier.Thelattermay
facilitatethepassageofneurotoxinsintothebrain.Putativeneurotoxinsinclude
shortchainfattyacids,mercaptans,falseneurotransmitters(eg,tyramine,
octopamine,betaphenylethanolamines),ammonia,andgammaaminobutyricacid
(GABA).
Ammoniahypothesis
AmmoniaisproducedintheGItractbybacterialdegradationofamines,amino
acids,purines,andurea.Normally,ammoniaisdetoxifiedintheliverbyconversion
toureaandglutamine.Inliverdiseaseorportosystemicshunting,portalblood
ammoniaisnotconvertedefficientlytourea.Increasedlevelsofammoniamayenter
thesystemiccirculationbecauseofportosystemicshunting.
Ammoniahasmultipleneurotoxiceffects,includingalterationofthetransitofamino
acids,water,andelectrolytesacrosstheneuronalmembrane.Ammoniaalsocan
inhibitthegenerationofexcitatoryandinhibitorypostsynapticpotentials.Therapeutic
strategiestoreduceserumammonialevelstendtoimprovehepaticencephalopathy.
However,approximately10%ofpatientswithsignificantencephalopathyhave
normalserumammonialevels.Furthermore,manypatientswithcirrhosishave
elevatedammonialevelswithoutevidenceofencephalopathy.
Gammaaminobutyricacidhypothesis
GABAisaneuroinhibitorysubstanceproducedintheGItract.Itwaspostulatedthat
GABAcrossestheextrapermeablebloodbrainbarriersofpatientswithcirrhosisand
theninteractswithsupersensitivepostsynapticGABAreceptors.[33]Thiswouldlead
tothegenerationofinhibitorypostsynapticpotentials.Clinically,thisinteractionwas
believedtoproducethesymptomsofhepaticencephalopathy.Subsequentworkhas
suggestedthatbrainGABAlevelsarenotincreasedinpatientswithcirrhosis.
However,brainlevelsofneurosteroidsareincreasedinpatientswithcirrhosis.[34]
TheyarecapableofbindingtotheirreceptorwithintheneuronalGABAreceptor
complexandcanincreaseinhibitoryneurotransmission.Someinvestigators
currentlycontendthatneurosteroidsmayplayakeyroleinhepaticencephalopathy.
[35]

Clinicalfeatures
Thesymptomsofhepaticencephalopathymayrangefrommildtosevereandmay
beobservedinasmanyas70%ofpatientswithcirrhosis.Symptomsaregradedon
thefollowingscale:
Grade0Subclinicalnormalmentalstatusbutminimalchangesinmemory,
concentration,intellectualfunction,coordination
Grade1Mildconfusion,euphoriaordepression,decreasedattention,
slowingofabilitytoperformmentaltasks,irritability,disorderofsleeppattern
(ie,invertedsleepcycle)
Grade2Drowsiness,lethargy,grossdeficitsinabilitytoperformmental
tasks,obviouspersonalitychanges,inappropriatebehavior,intermittent
disorientation(usuallywithregardtotime)
Grade3Somnolent,butarousable,stateinabilitytoperformmentaltasks
disorientationwithregardtotimeandplacemarkedconfusionamnesia
occasionalfitsofragespeechispresentbutincomprehensible
Grade4Coma,withorwithoutresponsetopainfulstimuli
Patientswithmildandmoderatehepaticencephalopathydemonstratedecreased
shorttermmemoryandconcentrationonmentalstatustesting.Findingsonphysical
examinationincludeasterixisandfetorhepaticus.

Laboratoryabnormalities
Anelevatedarterialorfreevenousserumammonialevelistheclassiclaboratory
abnormalityreportedinpatientswithhepaticencephalopathy.Thisfindingmayaidin
theassignmentofacorrectdiagnosistoapatientwithcirrhosiswhopresentswith
alteredmentalstatus.
However,serialammoniameasurementsareinferiortoclinicalassessmentin
gaugingimprovementordeteriorationinpatientsundertherapyforhepatic
encephalopathy.Noutilityexistsforcheckingtheammonialevelinapatientwith
cirrhosiswhodoesnothavehepaticencephalopathy.
Somepatientswithhepaticencephalopathyhavetheclassic,butnonspecific,
electroencephalogram(EEG)changesofhighamplitudelowfrequencywavesand
triphasicwaves.Electroencephalographymaybehelpfulintheinitialworkupofa
patientwithcirrhosisandalteredmentalstatus,whenrulingoutseizureactivitymay
benecessary.
CTscanandMRIstudiesofthebrainmaybeimportantinrulingoutintracranial
lesionswhenthediagnosisofhepaticencephalopathyisinquestion.

Commonprecipitants
Somepatientswithahistoryofhepaticencephalopathyhavenormalmentalstatus
whenundermedicaltherapy.Othershavechronicmemoryimpairmentinspiteof
medicalmanagement.Bothgroupsofpatientsaresubjecttoepisodesofworsened
encephalopathy.Commonprecipitantsofhyperammonemiaandworseningmental
statusareasfollows:

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Diuretictherapy
Hypovolemia
Renalfailure
GIbleeding
Infection
Constipation
Dietaryproteinoverloadisaninfrequentcauseofworseningencephalopathy.
Medications,notablyopiates,benzodiazepines,antidepressants,andantipsychotic
agents,alsomayworsenencephalopathicsymptoms.

Differentialdiagnosis
Conditionstoconsiderinthedifferentialdiagnosisofencephalopathyincludethe
following:
IntracraniallesionsEg,subduralhematoma,intracranialbleeding,
cerebrovascularaccident,tumor,abscess
InfectionsEg,meningitis,encephalitis,abscess
MetabolicencephalopathyEg,hypoglycemia,electrolyteimbalance,anoxia,
hypercarbia,uremia
HyperammonemiafromothercausesEg,secondaryto
ureterosigmoidostomy,inheritedureacycledisorders
ToxicencephalopathyduetoalcoholEg,acuteintoxication,alcohol
withdrawal,Wernickeencephalopathy
ToxicencephalopathyduetodrugsEg,sedativehypnotics,
antidepressants,antipsychoticagents,salicylates
Organicbrainsyndrome
Postseizureencephalopathy

Management
Nonhepaticcausesofalteredmentalfunctionmustbeexcludedinpatientswith
cirrhosiswhohaveworseningmentalfunction.Acheckofthebloodammonialevel
maybehelpfulinsuchpatients.Medicationsthatdepresscentralnervoussystem
(CNS)function,especiallybenzodiazepines,shouldbeavoided.Precipitantsof
hepaticencephalopathyshouldbecorrected(eg,hypovolemia,metabolic
disturbances,GIbleeding,infection,constipation).
Lactulose
Lactuloseishelpfulinpatientswithanacuteonsetofsevereencephalopathy
symptomsandinpatientswithmilder,chronicsymptoms.Thisnonabsorbable
disaccharidestimulatesthepassageofammoniafromtissuesintothegutlumen
andinhibitsintestinalammoniaproduction.Initiallactulosedosingis30mLorally
onceortwicedaily.Dosingisincreaseduntilthepatienthas24loosestoolsper
day.Dosingshouldbereducedifthepatientcomplainsofdiarrhea,abdominal
cramping,orbloating.
Higherdosesoflactulosemaybeadministeredviaeitheranasogastricorrectal
tubetohospitalizedpatientswithsevereencephalopathy.Othercathartics,including
coloniclavagesolutionsthatcontainpolyethyleneglycol(PEG)(eg,GoLytely),also
maybeeffectiveinpatientswithsevereencephalopathy.
Inastudy,Sharmaetalconcludedthattheuseoflactuloseeffectivelyprevents
hepaticencephalopathyrecurrenceincirrhosis.Patientswithcirrhosisrecovering
fromhepaticencephalopathywererandomizedtoreceivelactulose(n=61)or
placebo(n=64).Overamedianfollowupof14months,12patients(19.6%)inthe
lactulosegroupdevelopedhepaticencephalopathy,comparedwith30patients
(46.8%)intheplacebogroup.[36]
Antibiotics
Neomycinandotherantibiotics(eg,metronidazole,oralvancomycin,paromomycin,
oralquinolones)serveassecondlineagents.Theyworkbydecreasingthecolonic
concentrationofammoniagenicbacteria.Neomycindosingis2501000mgorally24
timesdaily.Treatmentwithneomycinmaybecomplicatedbyototoxicityand
nephrotoxicity.
Rifaximin(Xifaxan,SalixPharmaceuticals,Inc,Morrisville,NC)isanonabsorbable
antibioticthatreceivedFDAapprovalin2004forthetreatmentoftravelers'diarrhea
andwasgivenapprovalin2010forthereductionofrecurrenthepatic
encephalopathy.Itsuseisalsobeingstudiedinirritablebowelsyndrome.Datafrom
Europesuggestthatrifaximincandecreasecoloniclevelsofammoniagenic
bacteria,withresultingimprovementinthesymptomsofhepaticencephalopathy.
Adoubleblind,placebocontrolledtrial,indicatedthatrifaximincanpreventthe
occurrencehepaticencephalopathy.Inthestudy,299patientswhoserecurrent
hepaticencephalopathywasinremissionreceivedeitherrifaximin550mgorplacebo
twicedaily.Eachgroupalsoreceivedlactulose.Breakthroughepisodesofhepatic
encephalopathyoccurredin22%ofpatientstreatedwithrifaximinandin46%of
patientswhoweregivenplacebo,whilehepaticencephalopathyrelated
hospitalizationoccurredin14%ofrifaximinpatientsandin23%ofplacebopatients.
[37]Rifaximinalsoappearedtobemoreeffectivethanlactuloseintrialsthat
comparedthe2drugsheadtohead.[38]
Otherdrugs
OtherchemicalscapableofdecreasingbloodammonialevelsareLornithineL
aspartate(availableinEurope)andsodiumbenzoate.[39]
Proteinrestriction
Lowproteindietswererecommendedroutinelyinthepastforpatientswithcirrhosis.
Highlevelsofaromaticaminoacidscontainedinanimalproteinswerebelievedto
leadtoincreasedbloodlevelsofthefalseneurotransmitterstyramineand
octopamine,withresultantworseningofencephalopathicsymptoms.Inthisauthor's

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experience,thevastmajorityofpatientscantolerateaproteinrichdiet(>1.2g/kg
daily)thatincludeswellcookedchicken,fish,vegetableprotein,and,ifneeded,
proteinsupplements.
Proteinrestrictionisrarelynecessaryinpatientswithsymptomsofchronic
encephalopathy.Manypatientswithcirrhosishaveproteincaloriemalnutritionat
baselinetheroutinerestrictionofdietaryproteinintakeincreasestheirriskfor
worseningmalnutrition.
Intheauthor'sopinion,proteinrestrictionisinfrequentlyvaluableinpatientswithan
acuteflareupofsymptomsofhepaticencephalopathy.Onestudyrandomized
hospitalizedpatientswithhepaticencephalopathytoreceiveeitheranormalprotein
dietoralowproteindiet,inadditiontostandardtreatmentmeasures,andfoundno
differencebetweenthe2groupsinoutcomesforhepaticencephalopathy.[40]

OtherManifestationsofCirrhosis
Allchronicliverdiseasesthatprogresstocirrhosishaveincommonthehistologic
featuresofhepaticfibrosisandnodularregeneration.However,patients'signsand
symptomsmayvary,dependingontheunderlyingetiologyofthedisease.
Asanexample,patientswithendstageliverdiseasecausedbyhepatitisCmay
developprofoundmusclewasting,markedascites,andseverehepatic
encephalopathy,withonlymildjaundice.Incontrast,patientswithendstageprimary
biliarycirrhosismaybedeeplyicteric,withnoevidenceofmusclewasting.These
patientsmaycomplainofextremefatigueandpruritusandhavenocomplicationsof
portalhypertension.Inbothcases,medicalmanagementisfocusedonthereliefof
symptoms.Livertransplantationshouldbeconsideredasapotentialtherapeutic
option,giventheinexorablecourseofmostcasesofendstageliverdisease.
Manypatientswithcirrhosisexperiencefatigue,anorexia,weightloss,andmuscle
wasting.Cutaneousmanifestationsofcirrhosisincludejaundice,spiderangiomata,
skintelangiectasias(termed"papermoneyskin"byDameSheilaSherlock),palmar
erythema,whitenails,disappearanceoflunulae,andfingerclubbing,especiallyin
thesettingofhepatopulmonarysyndrome.
Patientswithcirrhosismayexperienceincreasedconversionofandrogenicsteroids
intoestrogensinskin,adiposetissue,muscle,andbone.Malesmaydevelop
gynecomastiaandimpotence.Lossofaxillaryandpubichairisnotedinmenand
women.Hyperestrogenemiaalsomayexplainspiderangiomataandpalmar
erythema.

Hematologicmanifestations
Anemiamayresultfromfolatedeficiency,hemolysis,orhypersplenism.[41]
Thrombocytopeniausuallyissecondarytohypersplenismanddecreasedlevelsof
thrombopoietin.Coagulopathyresultsfromdecreasedhepaticproductionof
coagulationfactors.Ifcholestasisispresent,decreasedmicelleentryintothesmall
intestineleadstodecreasedvitaminKabsorption,withresultingreductioninhepatic
productionoffactorsII,VII,IX,andX.Patientswithcirrhosisalsomayexperience
fibrinolysisanddisseminatedintravascularcoagulation.

Pulmonaryandcardiacmanifestations
Patientswithcirrhosismayhaveimpairedpulmonaryfunction.Pleuraleffusionsand
thediaphragmaticelevationcausedbymassiveascitesmayalterventilation
perfusionrelations.Interstitialedemaordilatedprecapillarypulmonaryvesselsmay
reducepulmonarydiffusingcapacity.
Patientsalsomayhavehepatopulmonarysyndrome(HPS).Inthiscondition,
pulmonaryarteriovenousanastomosesresultinarteriovenousshunting.HPSisa
potentiallyprogressiveandlifethreateningcomplicationofcirrhosis.ClassicHPSis
markedbythesymptomofplatypneaandthefindingoforthodeoxia,butthe
syndromemustbeconsideredinanypatientwithcirrhosiswhohasevidenceof
oxygendesaturation.
HPSisdetectedmostreadilybyechocardiographicvisualizationoflateappearing
bubblesintheleftatriumfollowingtheinjectionofagitatedsaline.Patientscan
receiveadiagnosisofHPSwhentheirPaO2islessthan70mmHg.Somecasesof
HPSmaybecorrectedbylivertransplantation.Infact,apatient'scoursetoliver
transplantationmaybeexpeditedwhenhisorherPaO2islessthan60mmHg.
Portopulmonaryhypertension(PPHTN)isobservedinupto6%ofpatientswith
cirrhosis.Itsetiologyisunknown.PPHTNisdefinedasthepresenceofamean
pulmonaryarterypressureofgreaterthan25mmHginthesettingofanormal
pulmonarycapillarywedgepressure.
RoutineDopplerechocardiographyisperformedaspartofmanylivertransplant
programstoruleouttheintervaldevelopmentofPPHTNinpatientsonthe
transplantwaitinglist.Indeed,thepresenceofameanpulmonarypressureof
greaterthan35mmHgsignificantlyincreasestherisksoflivertransplantsurgery.
PatientswhodevelopseverePPHTNmayrequireaggressivemedicaltherapyinan
efforttostabilizepulmonaryarterypressuresandtodecreasetheirchanceof
perioperativemortality.

Hepatocellularcarcinomaandcholangiocarcinoma
Hepatocellularcarcinoma(HCC)ultimatelyarisesin1025%ofpatientswith
cirrhosisintheUnitedStates.Ittypicallyoccursinaboutof3%ofpatientsperyear,
whentheetiologyofcirrhosisishepatitisB,hepatitisC,oralcohol.Itdevelopsmore
commonlyinpatientswithunderlyinghereditaryhemochromatosisoralpha1
antitrypsindeficiency.HCCisobservedlesscommonlyinprimarybiliarycirrhosis
andisararecomplicationofWilsondisease.
Cholangiocarcinomaoccursinapproximately10%ofpatientswithprimary

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sclerosingcholangitis.EarlydiagnosisofHCCiscriticalbecauseitispotentially
curablethrougheitherliverresectionorlivertransplant.

Otherdiseases
Otherconditionsthatappearwithincreasedincidenceinpatientswithcirrhosis
includepepticulcerdisease,diabetes,andgallstones.

AssessmentoftheSeverityofCirrhosis
Formanyyears,themostcommonprognostictoolusedinpatientswithcirrhosis
wastheChildTurcottePugh(CTP)system.ChildandTurcottefirstintroducedtheir
scoringsystemin1964asameansofpredictingtheoperativemortalityassociated
withportocavalshuntsurgery.Pugh'srevisedsystemin1973substitutedalbuminfor
thelessspecificvariableofnutritionalstatus.[42]Subsequentrevisionshaveused
theInternationalNormalizedRatio(INR)inadditiontoprothrombintime.
EpidemiologicworkshowsthattheCTPscoremaypredictlifeexpectancyin
patientswithadvancedcirrhosis.ACTPscoreof10orgreaterisassociatedwitha
50%chanceofdeathwithin1year.(SeeTable4,below.)
Table4.ChildTurcottePughScoringSystemforCirrhosis(OpenTableinanew
window)
ClinicalVariable

1Point

2Points

3Points

Encephalopathy

None

Grade12

Grade34

Ascites

Absent

Slight

Moderateor
large

Bilirubin(mg/dL)

<2

23

>3

BilirubininPBC*orPSC**(mg/dL) <4

410

10

Albumin(g/dL)

>3.5

2.83.5

<2.8

Prothrombintime(seconds
prolongedorINR)

<4sorINR
<1.7

46sorINR
1.72.3

>6sorINR
>2.3

*PBC=Primarybiliarycirrhosis

**PSC=Primarysclerosingcholangitis

ChildClassA=56points,ChildClassB=79points,ChildClassC=1015
points

Since2002,livertransplantprogramsintheUnitedStateshaveusedtheModelfor
EndStageLiverDisease(MELD)scoringsystemtoassesstherelativeseverityof
patients'liverdisease.PatientsmayreceiveaMELDscoreof640points(seethe
MELDScorecalculator).The3monthmortalitystatisticsareassociatedwiththe
followingMELDscores[43]:
MELDscoreoflessthan92.9%mortality
MELDscoreof10197.7%mortality
MELDscoreof202923.5%mortality
MELDscoreof303960%mortality
MELDscoreofgreaterthan4081%mortality

PharmacologicTreatment
Specificmedicaltherapiesmaybeappliedtomanyliverdiseasesinaneffortto
diminishsymptomsandtopreventorforestallthedevelopmentofcirrhosis.
Examplesincludeprednisoneandazathioprineforautoimmunehepatitis,interferon
andotherantiviralagentsforhepatitisBandC,[44]phlebotomyfor
hemochromatosis,ursodeoxycholicacidforprimarybiliarycirrhosis,andtrientine
andzincforWilsondisease.
Thesetherapiesbecomeprogressivelylesseffectiveifchronicliverdiseaseevolves
intocirrhosis.Oncecirrhosisdevelops,treatmentisaimedatthemanagementof
complicationsastheyarise.Certainlyvaricealbleeding,ascites,andhepatic
encephalopathyareamongthemostseriouscomplicationsexperiencedbypatients
withcirrhosis.However,attentionalsomustbepaidtopatients'chronic
constitutionalcomplaints.

Zincdeficiency
Zincdeficiencycommonlyisobservedinpatientswithcirrhosis.Treatmentwithzinc
sulfateat220mgorallytwicedailymayimprovedysgeusiaandcanstimulate
appetite.Furthermore,zinciseffectiveinthetreatmentofmusclecrampsandis
adjunctivetherapyforhepaticencephalopathy.

Pruritus
Pruritusisacommoncomplaintincholestaticliverdiseases(eg,primarybiliary
cirrhosis)andinnoncholestaticchronicliverdiseases(eg,hepatitisC).Although
increasedserumbileacidlevelsoncewerethoughttobethecauseofpruritus,
endogenousopioidsaremorelikelytobetheculpritpruritogen.Milditching
complaintsmayrespondtotreatmentwithantihistaminesandtopicalammonium
lactate.

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Cholestyramineisthemainstayoftherapyforthepruritusofliverdisease.Toavoid
compromisingGIabsorption,careshouldbetakentoavoidcoadministrationofthis
organicanionbinderwithanyothermedication.
Othermedicationsthatmayprovidereliefagainstpruritusincludeantihistamines
(eg,diphenhydramine,hydroxyzine),ursodeoxycholicacid,ammoniumlactate12%
skincream(LacHydrin,WestwoodSquibbPharmaceuticals,Inc,Princeton,NJ),
doxepin,andrifampin.Naltrexone,anopiate(anopioidantagonist),maybeeffective
butisoftenpoorlytolerated.Gabapentinisanunreliabletherapy.Patientswith
severepruritusmayrequireinstitutionofultravioletlighttherapyorplasmapheresis.

Hypogonadism
Somemalepatientssufferfromhypogonadism.Patientswithseveresymptomsmay
undergotherapywithtopicaltestosteronepreparations,althoughtheirsafetyand
efficacyisnotwellstudied.Similarly,theutilityandsafetyofgrowthhormone
therapyremainsunclear.

Osteoporosis
Patientswithcirrhosismaydeveloposteoporosis.Supplementationwithcalciumand
vitaminDisimportantinpatientsathighriskforosteoporosis,especiallypatients
withchroniccholestasisorprimarybiliarycirrhosisandpatientsreceiving
corticosteroidsforautoimmunehepatitis.Thediscoveryonbonedensitometry
studiesofdecreasedbonemineralizationmayprompttheinstitutionoftherapywith
anaminobisphosphonate(eg,alendronatesodium).

Vaccination
Patientswithchronicliverdiseaseshouldreceivevaccinationtoprotectthem
againsthepatitisA.Otherprotectivemeasuresincludevaccinationagainstinfluenza
andpneumococci.

Drughepatotoxicityinthepatientwithcirrhosis
Theinstitutionofanynewmedicaltherapywarrantstheperformanceofmore
frequentliverchemistriespatientswithliverdiseasecanillaffordtohavedrug
inducedliverdiseasesuperimposedontheircondition.Medicationsassociatedwith
druginducedliverdiseaseincludethefollowing:
Nonsteroidalantiinflammatorydrugs(NSAIDs)
Isoniazid
Valproicacid
Erythromycin
Amoxicillinclavulanate
Ketoconazole
Chlorpromazine
Ezetimibe
Statins
Hepatic3methylglutarylcoenzymeA(HMGCoA)reductaseinhibitorsarefrequently
associatedwithmildelevationsofalanineaminotransferase(ALT)levels.However,
severehepatotoxicityisreportedinfrequently.[45]Theliteraturesuggeststhatstatins
canbeusedsafelyinmostpatientswithchronicliverdisease.[46]Certainly,liver
chemistriesshouldbefollowedfrequentlyaftertheinitiationoftherapy.
Inastudyoftheeffectsofstatinsin58patientswithprimarybiliarycirrhosis,Rajab
andKaplanconcludedthatstatinuseissafeinpatientswiththiscondition.[47]
Individualsinthestudywereonstatinsforamedianperiodof41months,withALT
levelsmeasuredevery3months.Theauthorsfoundthattheselevelsdidnot
increase,beingslightlyelevatedwhenstatintreatmentbeganandnormalbythelast
followupanalysis.Patientsdidnotcomplainofmusclepainorweakness,and
serumcholesterollevelsfellby30%.
Analgesics
Theuseofanalgesicsinpatientswithcirrhosiscanbeproblematic.Althoughhigh
doseacetaminophenisawellknownhepatotoxin,mosthepatologistspermittheuse
ofacetaminopheninpatientswithcirrhosisatdosesofupto2000mgdaily.
NSAIDusemaypredisposepatientswithcirrhosistodevelopGIbleeding.Patients
withdecompensatedcirrhosisareatriskforNSAIDinducedrenalinsufficiency,
presumablybecauseofprostaglandininhibitionandworseningofrenalbloodflow.
Opiateanalgesicsarenotcontraindicatedbutmustbeusedwithcautioninpatients
withpreexistinghepaticencephalopathyonaccountofthedrugs'potentialtoworsen
underlyingmentalfunction.
Otherdrugs
Aminoglycosideantibioticsareconsideredobligatenephrotoxinsinpatientswith
cirrhosisandshouldbeavoided.Lowdoseestrogensandprogesteroneappearto
besafeinthesettingofliverdisease.
AreviewbyLewisandStineprovidedrecommendations,includingthefollowing,on
thesafeuseofmedicationsinpatientswithcirrhosis[48,49]:
Lowermedicationdosesshouldgenerallybeused,particularlyinpatients
withsignificantliverdysfunction
Protonpumpinhibitorsandhistamine2blockersshouldbeusedonlyfor
validindications,sincetheymayleadtoseriousinfectionsinpatientswith
cirrhosis

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Manypatientscomplainofanorexia,whichmaybecompoundedbythedirect
compressionofascitesontheGItract.Careshouldbetakentoensurethatpatients
receiveadequatecaloriesandproteinintheirdiets.Patientsfrequentlybenefitfrom
theadditionofcommonlyavailableliquidandpowderednutritionalsupplementsto
thediet.Onlyrarelycanpatientsnottolerateproteinsintheformofchicken,fish,
vegetables,andnutritionalsupplements.Institutionofalowproteindietoutof
concernthathepaticencephalopathymaydevelopplacesthepatientatriskfor
profoundmusclewasting.
The2010practiceguidelinesforalcoholicliverdiseasepublishedbytheAmerican
AssociationfortheStudyofLiverDiseasesandtheAmericanCollegeof
Gastroenterologyrecommendaggressivetreatmentofproteincaloriemalnutritionin
patientswithalcoholiccirrhosis.Multiplefeedingsperday,includingbreakfastanda
snackatnight,arespecified.[50]
Regularexercise,includingwalkingandevenswimming,shouldbeencouragedin
patientswithcirrhosis,topreventthesepatientsfromslippingintoaviciouscycleof
inactivityandmusclewasting.Debilitatedpatientsfrequentlybenefitfromaformal
exerciseprogramsupervisedbyaphysicaltherapist.

SurgicalRisks
Surgeryandgeneralanesthesiacarryincreasedrisksinthepatientwithcirrhosis.
Anesthesiareducescardiacoutput,inducessplanchnicvasodilation,andcausesa
3050%reductioninhepaticbloodflow.Thisplacesthecirrhoticliveratadditional
riskfordecompensation.
Surgeryissaidtobesafeinthesettingofmildchronichepatitis.Itsriskinpatients
withseverechronichepatitisisunknown.Patientswithwellcompensatedcirrhosis
haveincreased,butacceptable,morbidityandmortalityrisks.Careshouldbetaken
toavoidpostoperativeinfection,fluidoverload,unnecessarysedativesand
analgesics,andpotentiallyhepatotoxicandnephrotoxicdrugs(eg,aminoglycoside
antibiotics).
Intheprelaparoscopicera,astudyofnonshuntabdominalsurgeriesdemonstrateda
10%mortalityrateforpatientswithChildClassAcirrhosis,asopposedtoa30%
mortalityrateforpatientswithChildClassBcirrhosisanda75%mortalityratefor
patientswithChildClassCcirrhosis.[51]Althoughcholecystectomywasamongthe
riskiersurgeriesnoted,severalreportshavedescribedthesuccessfulperformance
oflaparoscopiccholecystectomyinpatientswithChildClassAorBcirrhosis.[52]
StudieshaveusedtheMELDscoreasatoolinpredictingpostoperativeoutcomesin
abdominalsurgery(seetheMELDScorecalculator).Inonestudy,apreoperative
MELDscoreofgreaterthan14wasabetterpredictorofpostoperativedeaththan
ChildClassCstatus.[53]
Inastudyofpatientswithcirrhosiswhounderwentmajordigestive,orthopedic,or
cardiovascularsurgery,thepreoperativeMELDscoresandtheirassociated30day
postoperativemortalityrateswereasfollows[54]:
MELDscoreof7orless5.7%mortality
MELDscoreof81110.3%mortality
MELDscoreof121525.4%mortality
MELDscoreof162044%mortality
MELDscoreof212553.8%mortality
MELDscoreofgreaterthan2690%mortality
Thebenefitsandtherisksofsurgeryshouldbecarefullyweighedbeforeadvising
thepatientwithcirrhosistoundergosurgery.

LiverTransplantation
Livertransplantationhasemergedasanimportantstrategyinthemanagementof
patientswithdecompensatedcirrhosis.Patientsshouldbereferredforconsideration
oflivertransplantationafterthefirstsignsofhepaticdecompensation.
Advancesinsurgicaltechnique,organpreservation,andimmunosuppressionhave
resultedindramaticimprovementsinpostoperativesurvival.Intheearly1980s,the
percentageofpatientssurviving1yearand5yearsafterlivertransplantwereonly
70%and15%,respectively.Now,patientscananticipatea1yearsurvivalrateof
8590%anda5yearsurvivalrateofhigherthan70%.Qualityoflifeafterliver
transplantisgoodorexcellentinmostcases.

Contraindicationstotransplant
Contraindicationsforlivertransplantationincludeseverecardiovascularor
pulmonarydisease,activedrugoralcoholabuse,malignancyoutsidetheliver,
sepsis,orpsychosocialproblemsthatmightjeopardizepatients'abilitiestofollow
theirmedicalregimensaftertransplant.
Accordingtothe2010guidelinesforalcoholicliverdiseasefromtheAmerican
AssociationfortheStudyofLiverDiseases,patientswhoseendstageliverdisease
isalcoholrelatedshouldbeconsideredascandidatesfortransplantationaftera
medicalandpsychosocialevaluationthatincludesformalassessmentofthe
probabilityoflongtermabstinence.[50]
Thepresenceofthehumanimmunodeficiencyvirus(HIV)inthebloodstreamalsois
acontraindicationtotransplant.However,successfullivertransplantationsarenow
beingperformedinpatientswithnodetectableHIVviralloadduetoantiretroviral
therapy.[55]Additionalclinicalstudyisrequiredbeforelivertransplantationcanbe
offeredroutinelytosuchpatients.

Organallocation
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Approximately6500livertransplantsareperformedintheUnitedStateseachyear.
Anincreasingnumberoflivesaresavedeachyearbytransplant.However,the
numberofdiagnosedcasesofcirrhosisisrising,fueledinpartbythehepatitisC
epidemicandbythegrowingnumberofcasesofnonalcoholicfattyliverdisease
(NAFLD).Thishasresultedinadramaticincreaseinthenumberofpatientslistedas
candidatesforlivertransplantation.
Approximately1215%ofpatientslistedascandidatesdiewhilewaitingbecauseof
therelativelystaticnumberoforgandonations.Strategiestoimprovethecurrent
donororganshortageincludeprogramstoincreasepublicawarenessofthe
importanceoforgandonation,increaseduseoflivingdonorlivertransplantationfor
pediatricandadultrecipients,organdonationaftercardiacdeath,andtheuseof
extendedcriteriadonors(ECDs).
AnECD"deviatesinsomeaspectfromtheidealdonor."OneexampleofanECD
organisthehepatitisCinfectedliverwithminimalfibrosisthatistransplantedintoa
hepatitisCinfectedrecipient.Suchtransplantshavebeenperformedsuccessfully
foranumberofyears.OtherexamplesofECDsincludedonorsolderthan70years
anddonorswithrelativelyfattylivers.
Theneedforamoreefficientandequitablesystemoforganallocationresultedin
dramaticchangesinUnitedStatesorganallocationpolicyin2002.[56]Previously,
patientswhowereacceptedaslivertransplantcandidateswith79CTPpoints
(ChildClassB)receivedlowpriorityonthetransplantwaitinglistmaintainedbythe
UnitedNetworkforOrganSharing(UNOS).Patientswith10ormoreCTPpoints
(ChildClassC)receivedahigherpriority.EmergentlivertransplantationatUNOS
status1wasreservedprimarilyfornoncirrhoticpatientssufferingfromfulminant
hepaticfailure.
Since2002,liversfromdeceaseddonors(ie,cadavericorgans)havebeenallocated
tocirrhoticpatientsusingtheMELDscoringsystemandthePediatricEndStage
LiverDisease(PELD)scoringsystem[43](seetheMELDScorecalculatorandthe
PELDScorecalculator).
IntheMELDscoringsystemforadults,apatientreceivesascorebasedonthe
followingformula:
MELDscore=0.957xLoge(creatininemg/dL)+0.378xLoge(bilirubinmg/dL)+
1.120xLoge(INR)+0.643
Asanexample,acirrhoticpatientwithacreatininelevelof1.9mg/dL,abilirubinlevel
of4.2mg/dL,andanINRof1.2wouldreceivethefollowingscore:
MELDscore=(0.957xLoge1.9)+(0.378xLoge4.2)+(1.120xLoge1.2)+0.643
=2.039
Thatvalueisthenmultipliedby10togivethepatientariskscoreof20.Patients'
MELDscoresarerecalculatedeverytimetheyundergolaboratorytesting.Patients
maybeassignedamaximumMELDscoreof40points.
ThePELDsystemusesasomewhatdifferentformula:PELDscore=0.480xLoge
(totalbilirubinmg/dL)+1.857xLoge(INR)0.687xLoge(albuming/dL)+0.436if
thepatientisyoungerthan1year+0.667ifthepatienthasgrowthfailure(<2
standarddeviations).Thisvalueismultipliedby10togiveafinalriskscore.
Withinanyregionofthecountry,adonororganinaparticularABObloodgroupis
allocatedtothecirrhoticpatientwithinthesamebloodgroupwhohasthehighest
MELDorPELDscore.Specialruleshavebeendevelopedtoaddresspotentiallylife
threateningliverdiseasecomplications,suchashepatocellularcarcinomaand
hepatopulmonarysyndrome.Patientswiththeseconditions,aswellasother
exceptionalcases,canreceiveahigherMELDorPELDscorethanthatcalculated
fromcreatinine,bilirubin,andINRalone.
Thetimingofthetransplantsurgeryforpatientsonthetransplantwaitinglistisakey
issue.Typically,itisbelievedthattherisksofthetransplantmayexceedthebenefits
whentheMELDscoreislessthan15.However,whentheMELDscoreisgreater
than15,thebenefitsofthetransplanttypicallyexceedtherisks.[57]Needlesstosay,
therecanbemanyexceptionstothissocalledrule.

Livingdonorlivertransplantation
Theadventoflivingdonorlivertransplantation(LDLT)hasintroducedanewvariable
intoanydiscussionofthetimingoftransplantation.LDLThasthepotentialtomake
livertransplantationanelectiveprocedurenotonlyforthecirrhoticpatientwith
significantcomplicationsbutalsoforthecirrhoticpatientwithapoorqualityoflife.
LDLTbecamearealityforpediatricrecipientsin1988andforadultrecipientsa
decadelater.Theprocedurearosefromadvancesinsurgicaltechniqueanda
worseningshortageofdeceaseddonororgans.InLDLT,upto60%ofahealthy
volunteerdonor'slivercanbesurgicallyresectedandtransplantedintotheabdomen
ofarecipient.GraftsurvivalinLDLTrecipientsisonparwiththatseeninthe
recipientsofdeceaseddonororgans.
However,LDLThasitslimitations.Themostobviousproblemisthelow,butreal,
riskofseriousoperativecomplicationsforthehealthyvolunteerliverdonor.Itis
estimatedthatabout0.4%ofthemorethan3000healthyliverdonorsworldwide
overthelastdecadehavediedasaconsequenceoftheirsurgery.Thus,transplant
programsmustmaximizedonorsafety.Theymustalsoensurethatthebenefitsof
LDLTtothepotentialrecipientoffsettheriskstothedonor.
Furthermore,noteverypotentialrecipientissufficientlystabletoundergosafeand
effectiveLDLT.Indeed,therecipient'sriskofposttransplantmortalityincreases
whenhisorherMELDscoreisgreaterthan25.Intheauthor'sopinion,LDLTshould
notbeperformedinsuchrecipients.

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Theshortageofdonororganshasspurredinterestintheuseofliverallograftsfrom
nonheartbeatingdonors(NHBDs).Typically,anNHBDisanindividualwhohas
sustainedirreversibleneurologicdamagebutwhoseclinicalconditiondoesnotmeet
formalbraindeathcriteria.Knowingthis,aprospectivedonor'sfamilywillgive
consentforwithdrawalofcareandfororgandonation.Thedonoristhenbroughtto
theoperatingroom,withtheanticipationthatwithdrawalofventilatorsupportwill
resultinthecessationofthepatient'scardiopulmonaryfunction.Oncedeathis
declared,organprocurementsurgerycanproceed.
Incontrasttotheorganprocuredfromaheartbeatingdonor(HBD),theallograft
obtainedfromanNHBDmaybesubjecttoconsiderablewarmischemiatimebefore
itisperfusedwithcoldpreservativesolution.
Areviewcomparingtheresultsoflivertransplantationusingallograftsfrom144
NHBDsand26,856HBDsoveran8yearperiodfoundbetteroutcomesinHBD
transplantrecipients.[58]Oneand3yeargraftsurvivalrateswere70%and63%,
respectively,withorgansfromNHBDs,asopposedto80%and72%,respectively,
withorgansfromHBDs.Higherratesofprimarynonfunctionandretransplantation
wereseenintherecipientsofallograftsfromNHBDs.
Otherauthorshavedescribedahigherincidenceofhepaticarterystenosis,hepatic
abscesses,andbilomasintherecipientsofallograftsfromNHBDs.[59]Itispossible
thatimprovedresultswillbeseenbylimitingdonorage,byminimizingdonorwarm
ischemiatime,andbynotattemptingtotransplantliversfromNHBDsintorecipients
whoareseverelyill.

Thefutureoflivertransplantation
Excitingnewtechnicaladvancesalsomayhelptoimprovepatients'chancesof
survival.Inthefuture,expandeduseofhepatocytetransplantationmayoccur.Inthis
therapy,asplenicarterycatheterisusedtodeliverbillionsofcryopreserved
hepatocytesintothespleenofapatientwhohasendstageliverdisease.The
patientthenundergoesroutineimmunosuppression.Thisstrategyhasbeen
employedsuccessfullyinasmallnumberofpatientswithcirrhosisandfulminant
hepaticfailure(FHF)whowerenotcandidatesforlivertransplantsurgery.
BioartificialliversmayseeincreasedapplicationinthecareofpatientswithFHF
and,perhaps,cirrhosis.The2moststudieddevicesarecomposedof
semipermeablecapillaryhollowfibermembranesenclosedinaplasticshell.Either
humanC3Ahepatomacellsorpighepatocytesareattachedtotheexteriorsurface
ofthemembranesasbloodfromthepatientispumpedthroughthedevice.
Intracranialpressureandhepaticencephalopathyimprovedinsomepatientswith
FHFwhowereassistedwiththesedevices.However,currentlyavailablebioartificial
livershavenotyetfulfilledthegoalsofbiotransformingandremovingtoxinswhile
supplyingthepatientwithclottingfactorsandgrowthfactors.
Xenotransplantationmaycomeintouseduringthenextdecade.Todate,all
attemptsatxenotransplantationinhumanshavesufferedfromsevere,earlyhumoral
orlatecellularrejectionandhaveresultedinpatientdeath.Advancesingenetic
engineeringmayleadtothedevelopmentofswinewhoseliversaremorelikelyto
undergograftacceptancewhentransplantedintohumans.Oncethisobstacleis
overcome,adeterminationcanbemadeastowhetheraswineliverisaneffective
substituteforahumanliver.
Mostimportantly,themedicalworldawaitsthedevelopmentofmedicaltherapies
thatforestallthedevelopmentofhepaticfibrosislongbeforepatientsdevelop
cirrhosisanditscomplications.

PatientMonitoring
Patientswithcirrhosisshouldundergoroutinefollowupmonitoringoftheircomplete
bloodcount,renalandliverchemistries,andprothrombintime.Theauthor'spolicyis
tomonitorstablepatients34timesperyear.

Surveillanceofesophagealvarices
Theauthorperformsroutinediagnosticendoscopytodeterminewhetherthepatient
hasasymptomaticesophagealvarices.Followupendoscopyisperformedin2years
ifvaricesarenotpresent.Ifvaricesarepresent,treatmentisinitiatedwitha
nonselectivebetablocker(eg,propranolol,nadolol),aimingfora25%reductionin
heartrate.Suchtherapyofferseffectiveprimaryprophylaxisagainstnewonsetof
varicealbleeding.[60]Patientswithlargeesophagealvaricesshouldundergo
prophylacticendoscopicvaricealligation.

Surveillanceforhepatocellularcarcinoma
Theincidenceofhepatocellularcarcinoma(HCC)hasrisenintheUnitedStates.
ThepracticeguidelinesoftheAmericanAssociationfortheStudyofLiverDiseases
recommendthatpatientswithcirrhosisundergosurveillanceforHCCwith
ultrasonographyevery6months.[61]Thediscoveryofalivernoduleshouldprompt
theperformanceofa4phaseCTscanoranMRIscan(ie,unenhanced,arterial,
venous,anddelayedphases).Lesionsthatenhanceinthearterialphaseandexhibit
"washout"inthedelayedphasesarehighlysuggestiveofHCC.
Manyauthorscontendthatthecombinationofarterialenhancementandwashouton
CTscanningorMRIoffersgreaterdiagnosticpowerforHCCthandoesguidedliver
biopsy.[62,63]Indeed,guidedliverbiopsieshavea2030%falsenegativeratein
makingthediagnosisofHCC.CurrentguidelinessupporttheuseofCTscanning
andMRIinconfirmingthepresenceofHCC.Biopsyisnotrequiredinordertodefine
alesionasHCC.[61]However,CTscanningorultrasonographicallyguidedliver
biopsymaybeusefulwhenanodulesenhancementcharacteristicsarenottypical
forHCC.
PatientswithadiagnosisofHCCandnoevidenceofextrahepaticdisease,as

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determinedbychestandabdominalCTscansandbybonescan,shouldbeoffered
curativetherapy.Commonly,thistherapyentailsliverresectionsurgeryforpatients
withChildClassAcirrhosisandanacceleratedcoursetolivertransplantationfor
patientswithChildClassBorCcirrhosis.
Patientswhoareawaitinglivertransplantationareoftenofferedminimallyinvasive
therapiesinanefforttokeeptumorsfromspreading.Thesetherapiesinclude
percutaneousinjectiontherapywithethanol,radiofrequencyandmicrowavethermal
ablation,chemoembolization,intensitymodulatedradiationtherapy,and
radioembolization.

ContributorInformationandDisclosures
Author
DavidCWolf,MD,FACP,FACG,AGAF,FAASLDMedicalDirectorofLiverTransplantation,Westchester
MedicalCenterProfessorofClinicalMedicine,DivisionofGastroenterologyandHepatobiliaryDiseases,
DepartmentofMedicine,NewYorkMedicalCollege
DavidCWolf,MD,FACP,FACG,AGAF,FAASLDisamemberofthefollowingmedicalsocieties:American
AssociationfortheStudyofLiverDiseases,AmericanCollegeofGastroenterology,AmericanCollegeof
Physicians,AmericanGastroenterologicalAssociation
Disclosure:ReceivedconsultingfeefromSalixforspeakingandteachingReceivedgrant/researchfundsfrom
IkariaforotherReceivedgrant/researchfundsfromVitalTherapiesforotherReceivedconsultingfeefromGilead
forspeakingandteachingReceivedconsultingfeefromAbbvieforspeakingandteaching.
ChiefEditor
BSAnand,MDProfessor,DepartmentofInternalMedicine,DivisionofGastroenterology,BaylorCollegeof
Medicine
BSAnand,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationfortheStudyofLiver
Diseases,AmericanCollegeofGastroenterology,AmericanGastroenterologicalAssociation,AmericanSociety
forGastrointestinalEndoscopy
Disclosure:Nothingtodisclose.
Acknowledgements
BSAnand,MDProfessor,DepartmentofInternalMedicine,DivisionofGastroenterology,BaylorCollegeof
Medicine
BSAnand,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationfortheStudyofLiver
Diseases,AmericanCollegeofGastroenterology,AmericanGastroenterologicalAssociation,andAmerican
SocietyforGastrointestinalEndoscopy
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment

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