OfficialreprintfromUpToDate

www.uptodate.com2017UpToDate

Cirrhosisinadults:Overviewofcomplications,generalmanagement,andprognosis

Authors: EricGoldberg,MD,SanjivChopra,MD,MACP
SectionEditor: BruceARunyon,MD
DeputyEditor: KristenMRobson,MD,MBA,FACG

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:May2017.|Thistopiclastupdated:Mar07,2017.

INTRODUCTIONCirrhosisrepresentsalatestageofprogressivehepaticfibrosischaracterizedbydistortionofthehepaticarchitecture
andtheformationofregenerativenodules.Itisgenerallyconsideredtobeirreversibleinitsadvancedstages,atwhichpointtheonly
optionmaybelivertransplantation.Inearlierstages,specifictreatmentsaimedattheunderlyingcauseofliverdiseasemayimproveor
evenreversecirrhosis.

Patientswithcirrhosisaresusceptibletoavarietyofcomplications,andtheirlifeexpectancycanbemarkedlyreduced.Cirrhosis
accountedforapproximately49,500deathsandwastheeighthleadingcauseofdeathintheUnitedStatesin2010[1].Inaddition,there
wereanestimated19,500deathsduetolivercancer,whichoftenoccursinthesettingofcirrhosis.Similarly,astudythatuseddatafrom
theNationalDeathIndexfromtheCentersforDiseaseControlandPreventionandtheRochesterEpidemiologyProjectestimatedthat
liverdiseasewasresponsiblefor66,007deathsin2008,ofwhich18,175wereduetohepatobiliarycancer[2].

Thistopicwillreviewthecomplications,generalmanagement,andprognosisofcirrhosis.Anoverviewofthecausesanddiagnosisof
cirrhosisispresentedseparately.(See"Cirrhosisinadults:Etiologies,clinicalmanifestations,anddiagnosis".)

MAJORCOMPLICATIONSMajorcomplicationsofcirrhosisinclude(table1):

Varicealhemorrhage
Ascites
Spontaneousbacterialperitonitis
Hepaticencephalopathy
Hepatocellularcarcinoma
Hepatorenalsyndrome
Hepatopulmonarysyndrome

Oncethesecomplicationsdevelop,patientsareconsideredtohavedecompensatedcirrhosis.Multiplefactorscanpredisposeto
decompensationinapatientwithcirrhosis.Riskfactorsfordecompensationincludebleeding,infection,alcoholintake,medications,
dehydration,andconstipation[35].Inaddition,patientswithobesityareatincreasedriskfordecompensation[6].Oncedecompensation
hasdeveloped,patientsshouldbeconsideredforlivertransplantation.(See"Livertransplantationinadults:Patientselectionand
pretransplantationevaluation"and"Livertransplantationinadults:Patientselectionandpretransplantationevaluation",sectionon
'Cirrhosis'.)

Othermajorcomplicationsofcirrhosisincludeportalveinthrombosisandcardiomyopathy.However,patientswiththesecomplications
alonearenotconsideredtohavedecompensatedcirrhosis.

Thissectionprovidesanoverviewofthecomplicationsofcirrhosis.Theindividualcomplicationsarediscussedindetailintheirrespective
topicreviews.

ComplicationsofportalhypertensionManyofthecomplicationsofcirrhosisaretheresultofportalhypertension(increased
pressurewithintheportalvenoussystem).Thiscanleadtotheformationofvenouscollaterals(varices)aswellascirculatory,vascular,
functional,andbiochemicalabnormalitiesthatcontributetothepathogenesisofascitesandothercomplications.(See"Portalhypertension
inadults"and"Pathogenesisofascitesinpatientswithcirrhosis",sectionon'Portalhypertension'.)

Complicationsofportalhypertensioninclude:

Ascites
Hepaticencephalopathy
Varicealhemorrhage
Spontaneousbacterialperitonitis
Hepatorenalsyndrome
Portalhypertensivegastropathy
Hepatichydrothorax
Hepatopulmonarysyndrome
Portopulmonaryhypertension
Cirrhoticcardiomyopathy
 VaricealhemorrhagePatientswithvaricealhemorrhagetypicallypresentwithhematemesisand/ormelena.Itistypicallytreated
withendoscopicvaricealbandligation.Othertreatmentsincludeendoscopicsclerotherapyandplacementofatransjugularintrahepatic
portosystemicshunt(TIPS).(See"Generalprinciplesofthemanagementofvaricealhemorrhage".)

Varicealhemorrhageisassociatedwithhighmortalityrates.Inthepast,themortalityrateofasinglevaricealhemorrhagewas30percent,
andonlyonethirdofpatientssurvivedforoneyear[7,8].Althoughsurvivalhasimprovedwithmoderntechniquesforcontrollingvariceal
hemorrhage,mortalityratesremainhigh(15to20percent30daymortality)[9].

PortalhypertensivegastropathyPortalhypertensivegastropathy(congestivegastropathy),whileextremelycommoninpatients
withportalhypertension,isanuncommoncauseofsignificantbleedinginthesepatients.Whenportalhypertensivegastropathyisthesole
causeofbleeding,thereisdiffusemucosaloozingwithnootherlesions,suchasvarices,toaccountfortheGIbleedingandanemia.The
mucosaisfriable,andbleedingpresumablyoccurswhentheectaticvesselsrupture.Theseverityofgastropathyisrelatedtothelevelof
portalpressure,thelevelofhepaticvascularresistance,andthedegreeofreductioninhepaticbloodflow(See"Portalhypertensive
gastropathy".)

AscitesAscitesistheaccumulationoffluidwithintheperitonealcavity.Itisthemostcommoncomplicationofcirrhosis.Thefirststep
leadingtofluidretentionandultimatelyascitesinpatientswithcirrhosisisthedevelopmentofportalhypertension.Patientswithoutportal
hypertensiondonotdevelopascitesoredema.Thosewithasciteshaveseveralcirculatory,vascular,functional,andbiochemical
abnormalitiesthatcontributetothepathogenesisoffluidretention.(See"Pathogenesisofascitesinpatientswithcirrhosis".)

Ascitesistypicallytreatedwithacombinationofdiureticsandsodiumrestriction,thoughsomepatientsrequirerepeatedtherapeutic
paracentesesorTIPSplacement.Amongpatientswithrefractoryascitesorspontaneousbacterialperitonitis,theuseofnonselectivebeta
blockersmaybeassociatedwithincreasedmortality[10,11].Thismayoccurbecausefailuretomaintainanadequatemeanarterialblood
pressureisstronglycorrelatedwithsurvivalinpatientswithadvancedcirrhosis.(See"Ascitesinadultswithcirrhosis:Initialtherapy"and
"Ascitesinadultswithcirrhosis:Diureticresistantascites",sectionon'Discontinuingbetablockers'and'Decompensatedcirrhosis'below
and"Spontaneousbacterialperitonitisinadults:Treatmentandprophylaxis",sectionon'Discontinuenonselectivebetablockers'.)

SpontaneousbacterialperitonitisSpontaneousbacterialperitonitis(SBP)isaninfectionofpreexistingasciticfluidwithout
evidenceforanintraabdominalsecondarysource,suchasaperforatedviscus.SBPisalmostalwaysseeninthesettingofendstage
liverdisease.ClinicalmanifestationsofSBPincludefever,abdominalpain,abdominaltenderness,andalteredmentalstatus.Some
patientsareasymptomaticandpresentwithonlymildlaboratoryabnormalities.(See"Spontaneousbacterialperitonitisinadults:Clinical
manifestations".)

TheindexofsuspicionforSBPmustbehighwithalowthresholdfordiagnosticparacentesis.Thediagnosisisestablishedbyapositive
asciticfluidbacterialcultureand/oranelevatedasciticfluidabsolutepolymorphonuclearleukocytecount(250cells/mm3).Withoutearly
antibiotictreatment,mortalityishigh.(See"Spontaneousbacterialperitonitisinadults:Diagnosis"and"Spontaneousbacterialperitonitisin
adults:Treatmentandprophylaxis".)

HepatorenalsyndromeHepatorenalsyndromereferstothedevelopmentofrenalfailureinapatientwhohasadvancedliver
diseaseduetocirrhosis,severealcoholichepatitis,acuteliverfailure,orlessoften,ametastatictumor.Ratherthanbeinganewdisease,
hepatorenalsyndromeusuallyrepresentstheendstageofasequenceofreductionsinrenalperfusioninducedbyincreasinglysevere
hepaticinjury.Arterialvasodilatationinthesplanchniccirculation,whichistriggeredbyportalhypertension,appearstoplayacentralrole
inthehemodynamicchangesandthedeclineinrenalfunctioninhepatorenalsyndrome.Theinitialreductionsinglomerularfiltrationrate
areoftenmaskedclinicallysinceassociateddecreasesinmusclemassandhepaticureaproductionminimizeelevationsintheplasma
creatinineconcentrationandbloodureanitrogen.(See"Hepatorenalsyndrome",sectionon'Pathogenesis'.)

Hepatorenalsyndromeischaracterizedbyagenerallybenignurinesediment,averylowrateofsodiumexcretion,andaprogressiverise
intheplasmacreatinineconcentration.Thereissomeconfusionregardingthepresenceorabsenceofoliguria.Thepercentageofpatients
witholiguriadependsuponthecutofffordefiningoliguria.Ifthecutoffis400mL/day,only44percentofpatientsareoliguric.If500
mL/dayisused,approximatelytwothirdsareoliguric.(See"Hepatorenalsyndrome",sectionon'Clinicalpresentation'.)

Thediagnosisisoneofexclusion,beingmadewhenothercausesofrenaldysfunctionhavebeenexcluded.Inparticular,volumedepletion
(aswithoverlyrapiddiuresis)canmimicallofthefindingsofhepatorenalsyndrome.Theprognosisispoorunlesshepaticfunction
improvesoralivertransplantationisperformed.(See"Hepatorenalsyndrome",sectionon'Diagnosis'and"Hepatorenalsyndrome",
sectionon'Treatment'.)

HepatichydrothoraxHepatichydrothoraxisdefinedasthepresenceofapleuraleffusioninapatientwithcirrhosisandno
evidenceofunderlyingcardiopulmonarydisease.Itresultsfromthemovementofasciticfluidintothepleuralspacethroughdefectsinthe
diaphragm,anditisusuallyrightsided.(See"Hepatichydrothorax".)

Thetreatmentforhepatichydrothoraxincludesdiureticsandsodiumrestriction.Patientswhodonotrespondtoconservativetherapymay
requirerepeatedtherapeuticthoracentesesorTIPS.Themostimportantaspectofmanagementisevaluationforlivertransplantation
(algorithm1).Chesttubesshouldnotbeplacedinpatientswithhepatichydrothorax.Placementofchesttubesinthissettingcanresultin
massiveproteinandelectrolytedepletion,infection,renalfailure,andbleeding.

HepatopulmonarysyndromeHepatopulmonarysyndrome(HPS)isdefinedbythefollowingtriad(see"Hepatopulmonary
syndromeinadults:Prevalence,causes,clinicalmanifestations,anddiagnosis"):

Liverdisease
 Increasedalveolararterialgradientwhilebreathingroomair
Evidenceforintrapulmonaryvascularabnormalities,referredtoasintrapulmonaryvasculardilatations

EstimatesoftheprevalenceofHPSamongpatientswithchronicliverdiseaserangefrom4to47percent,dependingonthediagnostic
criteriaandmethodsused.EveninthosewithoutHPS,mildhypoxemiaiscommonandispresumablycausedbyascites,withresulting
diaphragmaticelevationandventilation/perfusionmismatch.TherearenoeffectivemedicaltherapiesforHPS.Livertransplantationoffers
themostpromiseforsuccessfultreatment.(See"Hepatopulmonarysyndromeinadults:Naturalhistory,treatment,andoutcomes".)

PortopulmonaryhypertensionPortalhypertensionassociatedpulmonaryhypertension(portopulmonaryhypertension)refersto
thepresenceofpulmonaryhypertensioninpatientswithportalhypertension.Theprevalenceinpatientswithcirrhosisisapproximately2
percent[12].Neithertheprevalencenortheseverityofportopulmonaryhypertensionappearstocorrelatewiththedegreeofportal
hypertension[12].(See"Portopulmonaryhypertension".)

Patientswithportopulmonaryhypertensionmaypresentwithfatigue,dyspnea,peripheraledema,chestpain,andsyncope.Thediagnosis
maybesuggestedbyechocardiographyandconfirmedbyrightheartcatheterization.Patientswithmoderatetosevereportopulmonary
hypertensionaredifficulttotreatwithmedicaltherapy,andtheperioperativemortalitywithlivertransplantationishigh.

CirrhoticcardiomyopathyUpto50percentofpatientswithadvancedcirrhosishavefeaturesofcardiacdysfunction.Theterm
"cirrhoticcardiomyopathy"hasbeenusedtodescribesuchpatients,whoarecharacterizedashavingnormaltoincreasedcardiacoutput
andcontractilityatrest,butabluntedresponsetopharmacologic,physiologic,orpathologicstress[13].Patientsmayalsohave
electrophysiologicabnormalities.Itisthoughttoberelatedtobothportalhypertensionandcirrhosis.Cardiomyopathycanoccurfromany
causeofcirrhosis,althoughpatientswithalcoholismorhemochromatosismayhaveadditionalcontributingcausestocardiacdysfunction.
(See"Highoutputheartfailure",sectionon'Cirrhosis'and"Definitionandclassificationofthecardiomyopathies",sectionon'Cirrhotic
cardiomyopathy'.)

HepaticencephalopathyHepaticencephalopathydescribesthespectrumofpotentiallyreversibleneuropsychiatricabnormalitiesseen
inpatientswithliverdysfunction.Disturbanceinthediurnalsleeppattern(insomniaandhypersomnia)isacommonearlyfeaturethat
typicallyprecedesovertneurologicsigns(figure1andfigure2).Moreadvancedneurologicfeaturesincludethepresenceofasterixis,
hyperactivedeeptendonreflexes,and,lesscommonly,transientdecerebrateposturing.(See"Hepaticencephalopathyinadults:Clinical
manifestationsanddiagnosis".)

Treatmentsforhepaticencephalopathyincludeaddressinganypredisposingconditions(eg,infectionorgastrointestinalbleeding),
syntheticdisaccharides(eg,lactulose),andnonabsorbableantibiotics(eg,rifaximin).(See"Hepaticencephalopathyinadults:Treatment".)

HepatocellularcarcinomaPatientswithcirrhosishaveamarkedlyincreasedriskofdevelopinghepatocellularcarcinoma(HCC).
Patientswithmostformsofchronichepatitisarenotatanincreasedriskuntilcirrhosisdevelops.Exceptionstothisrulearepatientswith
chronichepatitisBvirusinfection,whocandevelopHCCintheabsenceofcirrhosis.(See"Epidemiologyandetiologicassociationsof
hepatocellularcarcinoma"and"Preventionofhepatocellularcarcinomaandrecommendationsforsurveillanceinadultswithchronicliver
disease".)

CertaincausesofcirrhosisappeartohavearelativelyincreasedriskforHCC.PatientswithcirrhosisfromhepatitisB,hepatitisC,
nonalcoholicsteatohepatitis,andhemochromatosisareatthehighestrisk,whilethosewithcirrhosisfromautoimmunehepatitisand
Wilsondiseaseappeartohavealowerrisk.(See"Epidemiologyandetiologicassociationsofhepatocellularcarcinoma",sectionon
'Chronichepatitisandcirrhosis'.)

Becauseofthelargefunctionalreserveoftheliver,patientswithHCCarefrequentlyasymptomaticearlyinitscourse,andthediagnosisis
oftendelayed.DecompensationinapatientwithpreviouslycompensatedcirrhosisshouldraisetheclinicalsuspicionthatHCChas
developed.OthercommonsignsandsymptomsofHCCareusuallyrelatedtomasseffectfromthetumorandincludepain,earlysatiety,
obstructivejaundice,andapalpablemass.HCCscanrupture,causinghemoperitoneum.Paraneoplasticmanifestationsinclude
erythrocytosis,hypercalcemia,hypoglycemia,anddiarrhea.(See"Clinicalfeaturesanddiagnosisofprimaryhepatocellularcarcinoma".)

ThediagnosisofHCCmaybesuggestedbymarkedelevationsofserumalphafetoprotein(AFP)orbycharacteristicradiographic
findings.ElevatedAFPisnotspecificforHCCsinceitcanalsobeseeninpatientswithacuteorchronichepatitis,gonadaltumors,and
pregnancy.However,risingserumAFPlevelsinapatientwithcirrhosisshouldraiseclinicalsuspicionforHCC.However,asignificant
proportionofpatientswithHCChavenormalAFPlevels,especiallywhenthetumorissmall.Asaresult,anormalAFPdoesnotpreclude
adiagnosis.(See"Clinicalfeaturesanddiagnosisofprimaryhepatocellularcarcinoma".)

PortalveinthrombosisPortalveinthrombosiscandevelopinpatientswithcirrhosisandcontributetothedevelopmentofportal
hypertension.Inpatientswithcirrhosis,thepathogenesisislikelyrelatedtounbalancedhemostasisandslowingofportalflow.Treatment
ofteninvolvesanticoagulation,thoughthedecisiontoanticoagulatemusttakeintoaccountthepatient'sriskforbleeding,particularlyif
esophagealvaricesarepresent.(See"Epidemiologyandpathogenesisofportalveinthrombosisinadults",sectionon'Pathogenesis'and
"Acuteportalveinthrombosisinadults:Clinicalmanifestations,diagnosis,andmanagement"and"Chronicportalveinthrombosisinadults:
Clinicalmanifestations,diagnosis,andmanagement".)

GENERALMANAGEMENTThemajorgoalsofmanagingpatientswithcirrhosisinclude:

Slowingorreversingtheprogressionofliverdisease
Preventingsuperimposedinsultstotheliver
Identifyingmedicationsthatrequiredoseadjustmentsorshouldbeavoidedentirely(table2andtable3)
 Managingsymptomsandlaboratoryabnormalities
Preventing,identifying,andtreatingthecomplicationsofcirrhosis
Determiningtheappropriatenessandoptimaltimingforlivertransplantation

SlowingorreversingtheprogressionofliverdiseaseAlthoughcirrhosisisgenerallyconsideredtobeirreversibleinitsadvanced
stages,theexactpointatwhichitbecomesirreversibleisunclear[14,15].Somechronicliverdiseasesrespondtotreatmentevenwhen
theliverdiseasehasprogressedtocirrhosis.Thus,specifictherapiesdirectedagainsttheunderlyingcauseofthecirrhosisshouldbe
instituted.

Asexamples:

PatientswithhepatitisCandadvancedfibrosisorcirrhosiswhoachieveasustainedvirologicresponse(SVR)withantiviraltreatment
havealowerriskofliverrelatedmortalitycomparedwithpatientswhodonotachieveanSVR[16].(See"Patientevaluationand
selectionforantiviraltherapyforchronichepatitisCvirusinfection",sectionon'Bridgingfibrosisandcompensatedcirrhosis'.)

Abstinencefromalcoholsubstantiallyimprovessurvivalinalcoholiccirrhosis.(See"Prognosisandmanagementofalcoholicfattyliver
diseaseandalcoholiccirrhosis",sectionon'Abstinence'.)

Successfultreatmentofchronicviralhepatitiscanimprovelongtermoutcomesandmayaffectfibrosis.Inastudyof91patientswith
chronichepatitisCandsignificantfibrosisbasedonliverelastography,patientswhoachievedasustainedvirologicresponsehada
significantdecreaseinliverstiffness(andthuspresumablyfibrosis)24weeksaftertheendoftreatment[17].(See"Noninvasive
assessmentofhepaticfibrosis:Ultrasoundbasedelastography".)

Preventingsuperimposedinsultstotheliver

VaccinationsVaccinationagainsthepatitisAandBforthosewhoarenotalreadyimmunecanhelppreventsuperimposedinsultsto
theliver.Othervaccinations,suchayearlyinfluenzavaccination,arealsorecommended(figure3).(See"Immunizationsforpatientswith
chronicliverdisease".)

AvoidanceofhepatotoxinsPatientswithcirrhosisshouldavoidmedications,supplements,andothersubstancesthatare
commonlyassociatedwithliverinjury.Thisincludesabusedsubstances,suchasalcohol,overthecountermedications(suchas
nonsteroidalantiinflammatorydrugs),prescribeddrugswithhepatotoxicsideeffects,andcertainherbalremedies.(See"Druginduced
liverinjury"and"Hepatotoxicityduetoherbalmedicationsanddietarysupplements".)

MedicationadjustmentsPatientswithcirrhosisareatincreasedriskofadverseeventswithmanymedicationsbecauseofimpaired
hepaticmetabolismorrenalexcretion.Manymedicationsrequiredoseadjustmentsorshouldbeavoidedentirely(table3andtable2)[18].

Issuesrelatedtotheuseofpainmedicationsinpatientswithcirrhosisarediscussedindetailelsewhere.(See"Managementofpainin
patientswithadvancedchronicliverdiseaseorcirrhosis".)

Managementofsymptomsandlaboratoryabnormalities

MusclecrampsPatientswithcirrhosismayexperiencemusclecramps,whichcanbesevere[1922].Thecauseisincompletely
understood,althoughtheymayberelatedtoareductionineffectivecirculatingplasmavolume,nervedysfunction,andalterationsin
energymetabolism[23].Ifotherdisordersareexcluded,treatmentsthatmaybehelpfulincludequininesulfate,branchedchainamino
acids,taurine,zincrepletion(forpatientswithlowlevels),andcorrectionofelectrolytes.Wepreferquininesulfateifpatientsareableto
obtainit(200to300mgatbedtime).(See"Nocturnallegcramps",sectionon'Causesandpathogenesis'.)

Inpatientssuspectedofhavingmusclecrampsrelatedtocirrhosis,othercausesofpainshouldbeexcluded.Musclecrampingrelatedto
cirrhosisisoftenspontaneous,chronic,andnocturnal.Ifthereisnewonsetofpersistentpain,otherdisorderssuchasrhabdomyolysis,
myositis,oracutekidneyinjuryshouldbeconsidered.

Quininesulfatehasbeenfoundtobebeneficialforthetreatmentofmusclecrampsinpatientswithcirrhosis,butitisnolongeravailable
throughpharmaciesfortreatmentofcrampsbecauseofsideeffectsincludingarrhythmiasandthrombocytopenia[24,25].However,itis
availablethroughsomeonlineretailers.Inametaanalysisthatincluded409patientswhocompletedparticipationinrandomizedtrials,
tinnituswastheonlysideeffectthatoccurredmoreoftenwithquininethanwithplacebo.Quininesulfatemayactbyreducingthe
excitabilityofthemotornerve[23].Notethatquininesulfateisnotthesameasquinidinesulfate(thelatterbeinganantiarrhythmicdrug).
(See"Nocturnallegcramps",sectionon'Management'.)

Othertreatmentshaveshownsomebenefitinsmallstudies.Theseincludebranchedchainaminoacids(4ggranulesthreetimesdaily)
[26,27],taurine(3goncedaily)[28,29],andvitaminE(200mgthreetimesdaily)[30].Branchedchainaminoacidsandtaurineare
thoughttoactbycorrectingalterationsinenergymetabolism,andvitaminEisthoughttodecreasecirculatingfreeradicalswithincells.
Correctingelectrolyteabnormalitiesisoftenrecommended,thoughitisnotknownwhetheritimprovessymptoms[23].

Zinchasbeenusedinthepastandmaybebeneficialinpatientswithlowzinclevels,thoughitsroleasatherapeuticagentremains
unclear[23,31].Whenused,ithasbeengivenas220mgtwicedaily.Magnesiumsupplementationhasnotspecificallybeenstudiedin
patientswithliverdisease,butitdoesnotappeartobebeneficialinpatientswithskeletalmusclecrampsingeneral[32].

Onesuggestedapproachtotreatmentis[23]:

Confirmthemusclecrampsarerelatedtocirrhosis
 Checkelectrolytelevelsandrepleteiflow
Treatwithbranchedchainaminoacidsifsymptomspersist
Treatwithtaurineifsymptomspersist
TreatwithvitaminEifsymptomspersist

Ourapproachistotreatwithquininesulfateifpatientscanobtainit.Ifnot,webelievetheaboveapproachisareasonablealternative.

UmbilicalherniasUmbilicalherniasposeamanagementdilemmainpatientswithcirrhosis,sincetheyoftendevelopinpatientswith
severeliverdiseaseandasciteswhoareathighriskofcomplicationswithsurgicalrepair[33].Successfulmanagementusingavarietyof
minimallyinvasivesurgicaltechniqueshasbeenreported[3438].However,clinicalexperiencehastemperedourenthusiasmforelective
surgicalrepair.Wehavewitnessedanunacceptablyhighcomplicationandrecurrencerateinourpatientsreferredforelectiverepair[39].
Livertransplantationsurgeonsprefertorepairherniasatthetimeoftransplantationandnotbeforebecausemanyhaveobservedhigh
postoperativemorbidityandmortalitywhenrepairwasperformedbeforethetransplantation.

Wehaveadoptedthefollowingapproachtomanagingumbilicalherniasinpatientswithcirrhosis:

Mostpatientswithrupturedorincarceratedherniasarereferredforimmediaterepair.However,ifincarcerationisdetectedearly,itcan
sometimesbereduced.

Patientswithsymptomaticherniasorthosewithmarkedthinningoftheskinoverlyingtheherniasac(asignofimpendingrupture),
especiallyifthereisweepingoffluidoranescharontheapexofthehernia,arereferredforelectiverepair.

Patientswithasymptomaticherniasaremanagedconservatively,withsurgicalcorrectionoftheherniaperformedatthetimeofliver
transplantation.Thecornerstoneofconservativemanagementinasymptomaticpatientswithumbilicalherniasisaggressive
managementofascites.Elastic/Velcroabdominalbinderscanalsohelpreducepainandminimizefurtherenlargementofthehernia.
(See"Ascitesinadultswithcirrhosis:Initialtherapy"and"Ascitesinadultswithcirrhosis:Diureticresistantascites".)

HyponatremiaHyponatremiaisacommonprobleminpatientswithadvancedcirrhosis.Thepathogenesisofhyponatremiais
directlyrelatedtothehemodynamicchangesandsecondaryneurohumoraladaptationsthatoccurinthesettingofcirrhosis,resultinginan
impairedabilitytoexcreteingestedwater.Theseverityofthehyponatremiaisrelatedtotheseverityofthecirrhosis.Themanagementof
hyponatremiaisdiscussedelsewhere.(See"Hyponatremiainpatientswithcirrhosis",sectionon'Treatment'.)

ThrombocytopeniaorelevatedINRPatientswithcirrhosisfrequentlyhavelowplateletcountsandelevatedinternational
normalizedratios(INRs).Becausethelivermakescoagulationfactorsaswellasanticoagulantproteins,liverdiseasecanleadtoa
hypocoagulablestateorahypercoagulablestate.Therelativebalanceorimbalanceofthesefactorsisnotreflectedinconventionalindices
ofcoagulation,suchastheprothrombintime,activatedpartialthromboplastintime,orINR.(See"Hemostaticabnormalitiesinpatientswith
liverdisease",sectionon'Effectsofhepaticdysfunction'.)

Patientstypicallyonlyneedtreatmentforthrombocytopeniaifaninvasiveprocedurethatisatmoderateorhighriskforbleedingis
planned,orinthesettingofactivebleeding.Itisreasonabletoaimforplateletcountsofatleast50,000/microLduringmoderaterisk
procedures[40]orinterventionsandplateletcountscloserto100,000/microLinhighrisksituationsorinthepresenceofactivebleeding
[41].(See"Hemostaticabnormalitiesinpatientswithliverdisease",sectionon'Invasiveprocedure'.)

Becauseconventionalindicesofcoagulationarenothelpfulindeterminingapatient'sbleedingrisk,patientswhorequireaninvasive
procedurethatisatmoderateorhighriskforbleedingorwhohaveactivebleedingmayneedadditionaltesting,suchasadeterminationof
fibrinogenlevels,thromboelastography,orthromboelastometrytoguidemanagement.Whileplasmaiscommonlygiventopatientswith
chronicliverdiseaseandanelevatedINR,plasmainfusionmayhaveadverseeffectsonportalveinpressuresandcollateralvesselflow.In
addition,thetraditionaldoseoftwounitsofplasmaisunlikelytosignificantlyaltercoagulationfactorlevels.(See"Clinicaluseofplasma
components",sectionon'Plasmaproducts'and"Hemostaticabnormalitiesinpatientswithliverdisease",sectionon'Commonclinical
problems'.)

Themanagementofpatientswithchronicliverdiseasewhorequireaninvasiveprocedurethatisatmoderateorhighriskforbleeding,or
whohaveactivebleeding,isdiscussedindetailelsewhere.(See"Hemostaticabnormalitiesinpatientswithliverdisease",sectionon
'Bleeding'and"Hemostaticabnormalitiesinpatientswithliverdisease",sectionon'Invasiveprocedure'.)

PreventingandidentifyingcomplicationsPatientsshouldbemonitoredforthedevelopmentofcomplications,andwhenpossible,
stepsshouldbetakentopreventtheirdevelopment.Inparticular,patientsshouldbescreenedforesophagealvaricesandhepatocellular
carcinoma.Ifvaricesarepresent,prophylactictreatmentwithbetablockersoresophagealvaricealligationisindicated.

Othermeasurestodecreasetheriskofcomplicationsincludejudiciousdiuresisandavoidingprotonpumpinhibitorsinpatientswithout
clearindicationsfortheiruse(spontaneousbacterialperitonitis)treatinginfections(spontaneousbacterialperitonitis,hepatic
encephalopathy)avoidingsedativesandtreatinghypokalemiaandhyponatremia(hepaticencephalopathy)avoidingnephrotoxicagents
andaggressivediuresis(hepatorenalsyndrome)andonlyusingurinarycatheters,mechanicalventilation,andcentrallineswhenclearly
indicated(secondaryinfections).(See'Majorcomplications'above.)

Varicealbleeding:Allpatientswithcirrhosisshouldundergoscreeningforesophagealvariceswithupperendoscopysothat
prophylactictherapycanbegiventothosewithvaricesthatareatincreasedriskforbleedingandtodeterminetheriskofvariceal
hemorrhage.Prophylactictherapymostcommonlyinvolvestreatmentwithanonselectivebetablockerorendoscopicvaricealligation,
 whichreducestheriskofvaricealbleeding.(See"Primaryandpreprimaryprophylaxisagainstvaricealhemorrhageinpatientswith
cirrhosis".)

Hepatocellularcarcinoma:Patientswithcirrhosisshouldundergosurveillancewithultrasonographyeverysixmonths.(See
"Preventionofhepatocellularcarcinomaandrecommendationsforsurveillanceinadultswithchronicliverdisease",sectionon
'Surveillancemethods'.)

Spontaneousbacterialperitonitis:Theriskofspontaneousbacterialperitonitis(SBP)canbereducedbyeffortstodiuresepatients
sincediuresisconcentratesasciticfluid,therebyraisingasciticfluidopsonicactivity.Earlyrecognitionandaggressivetreatmentof
localizedinfections(eg,cystitis,cellulitis)canalsohelptopreventbacteremiaandSBP.Protonpumpinhibitorusehasbeen
associatedwithanincreasedriskofSBP,soprotonpumpinhibitorsshouldonlybegiventopatientswhohaveclearindicationsfor
theiruse.Finally,prophylacticantibioticsaimedatdecontaminatingtheguthavearoleinspecificclinicalsettings.(See"Spontaneous
bacterialperitonitisinadults:Treatmentandprophylaxis".)

Hepaticencephalopathy:Patientswithcirrhosisshouldbeevaluatedregularlyforhepaticencephalopathy,theearliestfeaturesof
whichcanbesubtle.Eventsthatcanprecipitatehepaticencephalopathyincludethedevelopmentofvaricealbleeding,infection(such
asSBP),theadministrationofsedatives,hypokalemia,andhyponatremia,allofwhichshouldbecorrected/avoidedwhenever
possible(table4).(See"Hepaticencephalopathyinadults:Clinicalmanifestationsanddiagnosis"and"Hepaticencephalopathyin
adults:Treatment".)

Portalveinthrombosis:Enoxaparinmaybeeffectiveforpreventingportalveinthrombosis(PVT)inpatientswithcirrhosis,thoughit
isnotusedroutinely.Ifitistobeused,wesuggesteradicationofvarices(ifpresent)priortoinitiationofanticoagulationwhen
possible.(See"Chronicportalveinthrombosisinadults:Clinicalmanifestations,diagnosis,andmanagement",sectionon'Prevention
inpatientswithcirrhosis'and"Primaryandpreprimaryprophylaxisagainstvaricealhemorrhageinpatientswithcirrhosis",sectionon
'Endoscopicvaricealligation'.)

Hepatorenalsyndrome:Nephrotoxicagents(suchasaminoglycosides)andvigorousdiuresisshouldbeavoidedinpatientswith
cirrhosissincetheycanprecipitaterenalfailure.(See"Hepatorenalsyndrome".)

Secondaryinfections:Patientswithcirrhosiswhoarehospitalizedoftenacquireinfectionswhileinthehospital.Factorsthathave
beenassociatedwithhospitalacquiredsecondaryinfectionsinpatientswithcirrhosisincludetheuseofurinarycatheters,mechanical
ventilation,andtheplacementofcentrallines[42].Manyoftheseinterventionsareperformedroutinely(suchasplacementofurinary
catheterstomeasureurineoutput).However,avoidingtheseinterventionsunlesstheyareabsolutelynecessarymaydecreasethe
riskofacquiringaninfectionwhileinthehospital,anditisourpracticetoonlyusetheseinterventionswhenclearlyindicated.

Inastudyof207patientswithcirrhosiswhowereadmittedwithordevelopedaninfectionduringhospitalization,50(24percent)
developedasecondinfectionduringhospitalization[42].Respiratoryinfectionswerethemostcommon(14patients),followedby
urinarytractinfections(13patients),andClostridiumdifficile.Oftheurinarytractinfections,6(46percent)wererelatedtotheuseof
bladdercatheters.Otherfactorsassociatedwithsecondinfectionsincludedintensivecareunitadmission,theuseofcentrallines,
mechanicalventilation,shock,renalreplacementtherapy,andhepaticencephalopathy.Overallmortalitywas39percent,butitwas48
percentforthosewhodevelopedasecondinfectionduringadmission.

TreatmentofcomplicationsThetreatmentofthecomplicationsofcirrhosisisdiscussedintherespectivetopicreviews.(See'Major
complications'above.)

LivertransplantationLivertransplantationisthedefinitivetreatmentforpatientswithdecompensatedcirrhosis.Itisimportantto
determinewhetherpatientsmaybeeligiblefortransplantationandtoreferthemtoatransplantcenterforevaluation.Severalguidelines
areavailablewhichhelpdeterminewhenreferralforlivertransplantationmaybebeneficial.Thedecisiontoproceedtolivertransplantation
(eithercadavericorlivedonor)dependsupontheseverityofdisease,qualityoflife,andtheabsenceofcontraindications.(See"Liver
transplantationinadults:Patientselectionandpretransplantationevaluation".)

PROGNOSISTheprognosisofcirrhosisishighlyvariablesinceitisinfluencedbyanumberoffactors,includingetiology,severity,
presenceofcomplications,andcomorbiddiseases.Oncedecompensationoccurs(eg,thepatientdevelopsvaricealbleeding,hepatic
encephalopathy,orspontaneousbacterialperitonitis),mortalityratesarehigh.(See'Decompensatedcirrhosis'below.)

CompensatedcirrhosisPatientswithcirrhosiswhohavenotdevelopedmajorcomplicationsareclassifiedashavingcompensated
cirrhosis.Themediansurvivalofpatientswithcompensatedcirrhosisis>12years[43].Patientswithvaricesbutwhohavenotdeveloped
varicealbleedingareconsideredtohavecompensatedcirrhosis,thoughtheirprognosisisworsethanthatofpatientswhohave
compensatedcirrhosiswithoutvarices(3.4versus1.0percentoneyearmortalityrates)[43].

DecompensatedcirrhosisPatientswhohavedevelopedcomplicationsofcirrhosis,suchasvaricealhemorrhage,ascites,
spontaneousbacterialperitonitis,hepatocellularcarcinoma,hepatorenalsyndrome,orhepatopulmonarysyndrome,areconsideredto
havedecompensatedcirrhosisandhaveaworseprognosisthanthosewithcompensatedcirrhosis.(See'Majorcomplications'above.)

Asystematicreviewfoundthatthemediansurvivalwas6monthsinpatientswithdecompensatedcirrhosisandaChildPughscore12
oraModelforEndstageLiverDisease(MELD)score21[44].Inaddition,patientswithdecompensatedcirrhosiswhohadbeen
hospitalizedwithanacuteliverrelatedillness(eg,varicealhemorrhageorspontaneousbacterialperitonitis)hadamediansurvivalof6
monthsiftheChildPughscorewas12ortheMELDscorewas18.
Animportantfactorrelatedtosurvivalismeanarterialpressure.Inaseriesof139patientswithcirrhosisandascites,ameanarterial
pressureof82mmHgwasanimportantpredictorofsurvival[45].Amongpatientswithameanarterialpressure82mmHg,survivalwas
20percentat24monthsand0percentat48months(comparedwith70and50percent,respectively,forpatientswithameanarterial
pressure>82mmHg).

Anotherfactorthatmaybeassociatedwithsurvivalisthepresenceofrelativeadrenalinsufficiency[46,47].Inastudyof143patientswho
wereadmittedtothehospitalwithdecompensatedcirrhosis,relativeadrenalinsufficiencywasdetectedin37patients(26percent)[46].At
thetimeofpresentation,comparedwithpatientswhodidnothaverelativeadrenalinsufficiency,patientswithrelativeadrenalinsufficiency
hadlowermeanarterialpressures(76versus83mmHg)andserumsodiumlevels(131versus135mEq/L)andhadhigherbloodurea
nitrogenlevels(32versus24mg/dL).Duringthreemonthsoffollowup,patientswithrelativeadrenalinsufficiencyweremorelikelyto
developinfection(41versus21percent),severesepsis(27versus9percent),type1hepatorenalsyndrome(16versus3percent),and
death(22versus7percent).(See"Diagnosisofadrenalinsufficiencyinadults".)

Amongpatientswithcirrhosisandseveresepticshock,administrationofhydrocortisonemayimproveoutcomes[48].(See"Treatmentof
adrenalinsufficiencyinadults",sectionon'Glucocorticoidregimens'.)

Otherfactorsassociatedwithpoorsurvivalinpatientswithdecompensatedcirrhosisincludedhepatopulmonarysyndrome,rapidly
progressivehepatorenalsyndrome,andintensivecareunitadmissionforcomplicationsofliverdiseasealongwithhypotensionrequiring
pressorsupport,serumcreatinine>1.5mg/dL,orjaundice.

Patientswithdecompensatedcirrhosisoftenrequirelivertransplantation.Forthosewhoarenotcandidates,hospicecarecanbe
consideredforpatientswithpredictedsurvivalof6months.(See"Livertransplantationinadults:Patientselectionandpretransplantation
evaluation"and"Benefits,services,andmodelsofsubspecialtypalliativecare".)

PredictivemodelsMultiplestudieshaveattemptedtopredicttheprognosisofpatientswithcirrhosisbasedonclinicalandlaboratory
information.TwocommonlyusedmodelsaretheChildPughclassificationandMELD.

ChildPughclassificationTheChildPughclassification(table5)hasbeenusedtoassesstheriskofnonshuntoperationsin
patientswithcirrhosis(calculator1andcalculator2)[49].ItisamodificationoftheChildTurcotteclassification,whichincorporatedfive
variablesthatweredesignedtostratifytheriskofportacavalshuntsurgeryinpatientswithcirrhosis.Thevariablesincludedtheserum
albuminandbilirubin,ascites,encephalopathy,andnutritionalstatus(table6)[50].TheChildPughclassificationreplacesnutritionalstatus
withprothrombintime.Thescorerangesfrom5to15.Patientswithascoreof5or6haveChildPughclassAcirrhosis(wellcompensated
cirrhosis),thosewithascoreof7to9haveChildPughclassBcirrhosis(significantfunctionalcompromise),andthosewithascoreof10
to15haveChildPughclassCcirrhosis(decompensatedcirrhosis).

Inareviewof92patientswithcirrhosiswhounderwentabdominalsurgery,themortalityratewas10percentforpatientswithChildPugh
classAcirrhosis,30percentforpatientswithChildPughclassBcirrhosis,and82percentforpatientswithChildPughclassCcirrhosis
[51].OtherstudieshavevalidatedtheutilityoftheChildPughclassificationfortheassessmentofsurgicalrisk[52].(See"Assessing
surgicalriskinpatientswithliverdisease".)

TheChildPughclassificationsystemalsocorrelateswithsurvivalinpatientsnotundergoingsurgeryoneyearsurvivalratesforpatients
withChildPughclassA,B,andCcirrhosisareapproximately100,80,and45percent,respectively[53,54].ChildPughclassisalso
associatedwiththelikelihoodofdevelopingofcomplicationsofcirrhosis.Asanexample,patientswithChildPughclassCcirrhosisare
muchmorelikelytodevelopvaricealhemorrhagethanthosewithChildPughclassAcirrhosis[55].

MELDscoreAnothermodeltopredictprognosisinpatientswithcirrhosisistheMELDscore.Itisbaseduponbilirubinlevels,
creatinine,INR,andtheetiologyofcirrhosis(calculator3andcalculator4).TheMELDscorehasbeenadoptedforuseinprioritizing
patientsawaitinglivertransplantationandhasanexpandingroleinpredictingoutcomesinpatientswithliverdiseaseinthenon
transplantationsetting.InJanuary2016,OrganProcurementandTransplantationNetworkPolicy9.1(MELDScore)wasupdatedto
includeserumsodiumasafactorinthecalculationoftheMELDscore[56].TheMELDNascorecanbecalculatedonline.(See"Modelfor
EndstageLiverDisease(MELD)".)

WHENTOREFERTOASPECIALISTReferraltoahepatologistisrecommendedifthepatientdevelopsdecompensatedcirrhosisor
majorcomplicationsofcirrhosis.PatientswithaMELDscore10shouldbereferredtoalivertransplantationcenterforevaluation.In
addition,referraltoahepatologistshouldbeconsideredifthepatientrequirestreatmentfortheunderlyingcauseofthecirrhosis(eg,
hepatitisC,autoimmunehepatitis)oriftheclinicianmanagingthepatientwouldliketheassistanceofahepatologistinthepatient's
generalmanagement.(See"Livertransplantationinadults:Patientselectionandpretransplantationevaluation",sectionon'Cirrhosis'.)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"BeyondtheBasics."The
Basicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekey
questionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefer
short,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.These
articlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewith
somemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.
(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthekeyword(s)ofinterest.)

Basicstopics(see"Patienteducation:Cirrhosis(TheBasics)"and"Patienteducation:Livercancer(TheBasics)")
 BeyondtheBasicstopics(see"Patienteducation:Cirrhosis(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Cirrhosisrepresentsalatestageofprogressivehepaticfibrosischaracterizedbydistortionofthehepaticarchitectureandthe
formationofregenerativenodules.Itisgenerallyconsideredtobeirreversibleinitsadvancedstages.Inearlierstages,specific
treatmentsaimedattheunderlyingcauseofliverdiseasemayimproveorevenreversecirrhosis.(See'Introduction'above.)

Patientswithcirrhosisaresusceptibletoavarietyofcomplications,andtheirlifeexpectancycanbemarkedlyreduced.Major
complicationsofcirrhosisinclude(see'Majorcomplications'above):

Varicealhemorrhage
Ascites
Spontaneousbacterialperitonitis
Hepaticencephalopathy
Hepatocellularcarcinoma
Hepatorenalsyndrome
Hepatopulmonarysyndrome
Portalveinthrombosis
Cardiomyopathy

Themajorgoalsofmanagingpatientswithcirrhosisinclude(see'Generalmanagement'above):

Slowingorreversingtheprogressionofliverdisease(see'Slowingorreversingtheprogressionofliverdisease'above).
Preventingsuperimposedinsultstotheliver(see'Preventingsuperimposedinsultstotheliver'above).
Identifyingmedicationsthatrequiredoseadjustmentsorshouldbeavoidedentirely(table2andtable3)(see'Medication
adjustments'above).
Managingsymptomsandlaboratoryabnormalities(see'Managementofsymptomsandlaboratoryabnormalities'above).
Preventingandtreatingthecomplicationsofcirrhosis(see'Preventingandidentifyingcomplications'above).
Determiningtheappropriatenessandoptimaltimingforlivertransplantation(see'Livertransplantation'above).

Theprognosisofcirrhosisishighlyvariablesinceitisinfluencedbyanumberoffactors,includingetiology,severity,presenceof
complications,andcomorbiddiseases.Oncedecompensationoccurs(eg,thepatientdevelopsvaricealbleeding,hepatic
encephalopathy,orspontaneousbacterialperitonitis),mortalityratesarehigh.(See'Decompensatedcirrhosis'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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56.https://optn.transplant.hrsa.gov/news/meldserumsodiumpolicychanges/.

Topic1263Version32.0
GRAPHICS

Commoncomplicationsofcirrhosis

Varicealhemorrhage

Ascites

Spontaneousbacterialperitonitis

Hepaticencephalopathy

Hepatocellularcarcinoma

Hepatorenalsyndrome

Hepatopulmonarysyndrome

Hepatichydrothorax

Portopulmonaryhypertension

Cirrhoticcardiomyopathy

Portalveinthrombosis

Graphic65667Version3.0
Treatmentsforhepatichydrothorax

Allpatientswithconfirmedhepatichydrothoraxshouldbereferredforevaluation
forlivertransplantation.Thefirststepinmanagementistherapywithlow
sodiumdiet(88mEq[2000mg]perday)anddiuretics(seetopicreviewon
diuretictherapyforascites).Ifthereisnoresponsetodiuretics,therapeutic
thoracentesisofapproximately2literscanbeattemptedfollowedbydiuretics.If
patientsdonotrespondtodiureticsordevelopcomplications,theycanbe
consideredtohaverefractoryhepatichydrothoraxandshouldbeconsideredfor
transjugularintrahepaticportosystemicshunt(TIPS)placement.Thismeasure
mayhelpasabridgetolivertransplantation.However,patientsshouldbe
carefullyselected.TIPSisbestconsideredinpatientsyoungerthan70yearsof
age,withouthepaticencephalopathy,and/orthosewithChildA/Bcirrhosis.For
patientsthatcannotundergoTIPSplacement,considerationforpleurodesisor
diaphragmaticrepairbythoracoscopyshouldbeconsidered.Chesttube
placementshouldbeavoidedasitisassociatedwithseverecomplications.

*Furosemide40mg/dayandspironolactone100mg/day,andifthereisno
response,diureticsmaybeincreasedinastepwisefashioneverythreetofivedays
bydoublingdoses(ratioof40mg:100mg),furosemideupto160mg/dayand
spironolactoneupto400mg/day.

Graphic80148Version4.0
Evolutionofhepaticencephalopathy

Graphic58163Version1.0
Clinicalfeaturesofhepaticencephalopathy

Diagramdepictingthegradeofhepaticencephalopathyandtheclinicalfeaturesassociatedwith
advancingstages.

Datafrom:ConnHO,LieberthalMM.Thehepaticcomasyndromesandlactulose.LippincottWilliams&
Wilkins,Baltimore1979.

Graphic70740Version5.0
Medications(otherthananalgesics*)usedinadultpatientswithadvancedchronicliverdiseaseor
cirrhosis
Alteredresponseandpharmacokinetics
Alcoholabstinence
Baclofen Limitedhepaticmetabolism.
Preliminarysafetydataincirrhosisarepromising
however,efficacyisnotwellestablished.
Disulfiram Hepaticallymetabolizedandsubjecttonumerousdrug
interactions.
Reportsoffulminanthepatotoxicity.
Anticonvulsants
Carbamazepine Carbamazepineisapotentinducerofhepaticenzymes
andhasbeenassociatedwithhepatotoxicityand
seriousallergicreactionsingeneticallypredisposed
individuals.
Mayprecipitatedecompensationinpatentswith
cirrhosis.
Lamotrigine Halflifeisincreaseduptothreefoldinmoderateto
severehepaticimpairment.
Levetiracetam PKunalteredinliverdiseaseinpatientswithadequate
renalfunction(Crcl60mL/minute).
Drugaccumulationmayoccurinpatientswithrenal
insufficiencyandadvancedcirrhosis.
Oxcarbazepine PKseemstobeunalteredinmildtomoderatehepatic
impairmentwithadequaterenalfunction(Crcl30
mL/minute).
Phenytoin Extensivelymetabolizedinliverandapotentinducer
ofhepaticCYPenzymes.
Highlyboundtoserumalbuminhypoalbuminemic
patientswithadvancedCLDorcirrhosisgenerally
requirelowertotalplasmaconcentrationsforseizure
controlrelativetohealthyindividuals.
Topiramate Topiramateclearancecanbereducedinpatientswith
advancedCLDorcirrhosiswhoarealsoreceiving
enzymeinducingantiepilepticdrugsand/orwithrenal
insufficiency(Crcl<70mL/minute).
Metabolicacidosisisafrequentadverseeffectof
topiramatetreatment.RefertoUpToDatetopicreview
onpharmacologyofantiepilepticdrugs.
Valproate(valproicacid) Extensivelymetabolizedinliverandhighlyboundto
serumalbumin.
Drugaccumulationandtoxicityhasbeenobservedin
valproatetreatedpatientswithadvancedCLDor
cirrhosis.
Valproateassociatedhyperammonemiamaycomplicate
managementofHE.
Antidepressants
Bupropion Reducedclearanceandprolongedhalflifein
alcoholicsandinpatientswithseverehepatic
impairment.
Citalopram ExtensivelymetabolizedinliverbyCYPs2C19and
3A4.
Managementsuggestions
Totaldailydosetitratedto30to60mg,givenin
divideddoses,hasbeentoleratedbypatientswith
cirrhosis.
RefertoUpToDatetopicreviewofascitesinadults
withcirrhosisinitialtherapy,sectiononalcohol
abstinence.
Avoidorusewithextremecautionincirrhosis.
Ingeneral,carbamazepineshouldbeavoidedasthere
aresaferoptionsformanagementofseizuresin
patientswithadvancedCLDorcirrhosis.
Noadjustmentrequiredformildimpairment.
Reducedoseby25%formoderatetoseverehepatic
impairmentwithoutascites.
Reducedoseby50%formoderatetosevere
impairmentwithascites.
Noadjustmentrequiredforcompensatedcirrhosis.
Reducedosebyapproximately50%inpatientswith
advancedCLDandrenalinsufficiency(Crcl<60
mL/minute).
Nospecificadjustmentrecommendedfor
compensatedcirrhosiswithmildtomoderatehepatic
impairment.
Useinseverehepaticimpairmentordecompensated
diseaseisnotrecommendedasdataarelacking.
Ingeneral,phenytoinshouldbeavoidedinpatients
withcirrhosis.
Intheabsenceofothereffectiveoptionsforcontrolof
seizures,usecautiouslyincompensatedcirrhosis.
Avoidinpatientswhoareactivelyusingalcohol.
Freephenytoinlevelsmaybeusefulformonitoring
serumconcentrations.
RefertoUpToDatetopicreviewonpharmacologyof
antiepilepticdrugs.
Topiramatedoseadjustmentmaybeneededin
patientswithadvancedCLDorcirrhosisreceiving
enzymeinducingantiepilepticdrugsand/orrenal
impairment.
Druginteractionsbetweentopiramateandenzyme
inducingantiepilepticdrugsmaybeintensifiedin
hepaticimpairment.
Serumconcentrationmonitoringmaybeuseful.
Valproateshouldgenerallybeavoidedinadvanced
CLDorcirrhosis.
Useiscontraindicatedinseverehepaticimpairment.
Donotexceed75mgperday(immediaterelease),
100mgperday(sustainedrelease),or150mgevery
otherday(extendedrelease)inpatientswithearlyor
moderatecompensatedcirrhosis.
Avoidinsevereordecompensatedcirrhosisandin
patientsatriskforseizures.
Donotexceed20mgdaily.
 Exposure(plasmaconcentrationversustimecurve)
increasedtwofoldinsettingofcirrhosis.
Patientswithcirrhosis,particularlyifthereisaTIPS
orsurgicalshuntpresent,maybeatelevatedriskof
developingpotentiallyfatalventriculararrhythmiasdue
toQTprolongation.

Desvenlafaxine MetabolizedinliverprimarilybyUGTglucuronidation. Initiateat50mgdaily.Donotexceed100mgdaily.

PKunalteredinmildhepaticimpairment. Avoidindecompensatedcirrhosis,cirrhosiswithrenal
failure,andinpatientsatriskforseizures.

Duloxetine 85%reductioninclearanceandthreetofivefold AlcoholabuseorCLDmayberiskfactorsinduloxetine

increaseinhalflifeandexposure(plasma associatedhepatotoxicity.
concentrationversustimecurve)inmoderate Useshouldbeavoidedinhepaticimpairment.
cirrhosis.

Escitalopram ExtensivelymetabolizedinliverbyCYPs2C19and Initiateatalowdose(5mgdaily)forfirsttwoweeks

3A4. ormore.
Clearancereducedby37%,halflifeincreased Donotexceed10mgdaily.
approximatelytwofoldinsettingofcirrhosis.

Fluoxetine Reducedclearance. Reducedoseorfrequencyincirrhosisby50%.

Halflifeofactivemetabolitemayexceed12daysin
cirrhosis.
Newsteadystateconcentrationsmaynotbereached
untiltwoormoremonthsfollowingadose
adjustment.
Initiateatalowdose(eg,5or10mgdaily)andtitrate
graduallytopreventaccumulation.
Donotexceed20to40mgdailyinmildhepatic
impairment.

Fluvoxamine ExtensivelymetabolizedinliverbyCYP2D6and Reducedoseby50%.

undergoesfirstpassextraction. Initiateatalowdose(eg,25mgdaily)andtitrate
Oralbioavailabilityisincreasedandhalflifeprolonged graduallytopreventaccumulation.
to22to26hoursinsettingofcirrhosis. Donotexceed100mgdaily.

Mirtazapine Halflifeincreasedby40%andexposure(plasma Donotexceed30mgperday.

concentrationversustimecurve)increased
approximately55%inmildtomoderatehepatic
impairment.

Paroxetine ExtensivelymetabolizedinliverbyCYP2D6and Initiateat10mgdailyandtitrategradually.

undergoesfirstpassextraction. Donotexceed40mgdaily.
Halflifeprolongedandexposure(plasma
concentrationversustimecurve)increased
approximatelytwofoldinadvancedCLDorcirrhosis.

Sertraline ExtensivelymetabolizedinliverbyCYP2D6and Initiateat25mgdailyandtitrategraduallytoprevent

undergoesfirstpassextraction. accumulation.
Halflifeprolongedby2.5foldandexposure(plasma Donotexceed100mgdaily.
concentrationversustimecurve)increasedbyupto
fourfoldinadvancedCLDorcirrhosis.

Venlafaxine ExtensivelymetabolizedinliverbyCYP2D6and Initiateatalowdose(eg,37.5to75mgdaily)and

undergoesfirstpasshepaticextraction. titrategraduallytopreventaccumulation.Donot
WideinterindividualPKvariabilityseeninpatients exceed150mgdaily.
withcirrhosis. Avoidindecompensatedcirrhosis,cirrhosiswithrenal
Oralbioavailabilityisincreasedbytwotothreefoldin failure,andinpatientsatriskforseizures.
patientswithmildtomoderatehepaticimpairment.
Halflifeofvenlafaxineanditsactivemetabolitesis
prolongedbyupto1.4foldinmildtomoderate
hepaticimpairment.

Antipsychotics

Haloperidol ComplexhepaticmetabolismincludesCYP3A4and2D6 Nospecificdoseadjustment.

transformationsandactivemetabolites. Avoidwithactivealcoholconsumption.
ConsistentalterationofPKinhepaticimpairmenthas Avoidorusecautionwithalcoholwithdrawal
notbeenidentified. syndromeduetoriskofseizures.
Patientswithcirrhosis,particularlyifthereisaTIPS PreferabletobenzodiazepinesinpatientswithHE.
orsurgicalshuntpresent,maybeatelevatedriskof
developingpotentiallyfatalventriculararrhythmiasdue
toQTprolongation.

Olanzapine UndergoesextensivemetabolisminliverbyCYPs1A2 Inadvancedhepaticimpairmentinitiateorallyat5mg

and2D6. dailyandescalatedose,ifneeded,moregradually.
Halflifeisexpectedtobeincreasedinadvanced
hepaticimpairment.

Quetiapine UndergoesextensivemetabolisminliverbyCYP3A4. Initiateorallyat25mgdaily(immediaterelease)and

Halflifeisexpectedtobeincreasedinadvanced titrateinlowincrements(eg,25to50mgdaily)
hepaticimpairment. accordingtoresponse.

Antiinfectives

Antifungals

Azoles
 Azoleantifungalsarevariablymetabolizedinliver,and
allhavebeenassociatedwithhepaticfunction
abnormalities.
Ketoconazole,itraconazole,voriconazole,and
posaconazolehavepotentinhibitoryeffectsonhepatic
CYPmetabolism.
UseazoleswithcautioninadvancedCLDorcirrhosis.
Maintenancedosereductionandserumlevel
monitoringarerecommendedforvoriconazole.
Doseoffluconazoleshouldbeadjustedinadvanced
CLDorcirrhosiswithrenalinsufficiency.
AvoidketoconazoleinpatientswithCLD.
RefertoUpToDatetopicreviewofpharmacologyof
azoleantifungals.

Echinocandins Caspofunginandmicafunginundergohepatic Caspofunginrequiresdoseadjustmentinmoderate

metabolism.
Anidulafunginisnothepaticallymetabolizedalteration
ofPKduetoCLDorrenalinsufficiencyisnot
expected.
Modestasymptomaticincreasesinhepatic
transaminasesoccurinapproximately10%of
echinocandintreatedpatientswithoutCLD.
CLD.
Aspecificdoseadjustmentrecommendationfor
caspofunginisnotavailableforadvancedCLDor
cirrhosis.
Regularmonitoringofhepatictransaminasesis
suggestedduringechinocandintreatment.
RefertoUpToDatetopiconpharmacologyof
echinocandins.

Antimicrobials Hydrophilicantimicrobials(ie,aminoglycosides,betalactams,daptomycin,vancomycin)tendtoexhibitincreased
VdinpatientswithadvancedCLDorcirrhosiswithascitesorhypoalbuminemia.Loadingdose(s)andmonitoring
ofbloodconcentrationswhereavailableshouldbeconsideredfortreatingseriouslyillpatients.

Betalactams, Betalactamassociatedleukopeniamaycomplicate Monitorforbetalactamassociatedleukopenia.

carbapenems impairedreticularendothelialcellfunctioninadvanced
CLDorcirrhosis.

Fluoroquinolones Norfloxacin,ciprofloxacin,andlevofloxacinare Norfloxacin,levofloxacin,andciprofloxacindose

eliminatedrenallyanddonotundergoextensive shouldbeadjustedforadvancedCLDorcirrhosiswith
hepaticmetabolism.Levofloxacindistributesinascitic renalimpairment.RefertoLexicompmonographs.
fluid,butlessextensivelythancefotaxime. UsecautioninpatientswithprolongedQTintervals.
Patientswithcirrhosis,particularlyifthereisaTIPS
orsurgicalshuntpresent,maybeatelevatedriskof
developingpotentiallyfatalventriculararrhythmiasdue
toQTprolongation.

Macrolides Extensivelymetabolizedinliver. UseclarithromycinwithcautioninadvancedCLDor

Erythromycinestolate(notavailableinUnitedStates) cirrhosis.
maycausecholestasisinCLD. Avoiderythromycinestolate.
CertainmacrolidescanincreaseQTcinterval.

Metronidazole Metabolizedinliver,reducedclearanceandprolonged Increaseintervaltoevery12hoursinpatientswith

halflife(18to21hours)inadvancedCLDor advancedCLDorcirrhosis.
cirrhosis.

Tetracyclines Tetracyclinesaremetabolizedinliverandhalflifemay Reduceddoseshouldbeconsideredincompensated

beprolongedinadvancedCLDandcirrhosis. disease.
UsecautioninadvancedCLDorcirrhosis.
Ingeneral,avoidtetracyclinesindecompensated
cirrhosis.

Tigecycline Tigecyclineiseliminatedlargelybybiliaryexcretion Doseoftigecyclineshouldbeadjustedinsevere

anddoesnotundergoextensivemetabolisminthe hepaticimpairment.RefertoLexicompmonograph.
liver.

Trimethoprim Renallyexcreted. NodoseadjustmentrecommendedforCLDor

sulfamethoxazole PKappearsunalteredinmildtomoderatehepatic cirrhosiswithmildtomoderatehepaticimpairment.
(cotrimoxazole) impairment. Reducedoseinrenalinsufficiency.
Useshouldbeavoidedinseverehepaticimpairment
anddecompensateddiseaseaccordingtothelicensed
productinformation.

Antituberculosisdrugs IsoniazidmayaccumulateinadvancedCLDand Closelymonitorandconsiderdosereduction.

(isoniazid,pyrazinamide, cirrhosis. RefertoUpToDatetopicontreatmentofpulmonary
rifampin) Rifampiniseliminatedinbileandcanpotentially tuberculosisinHIVnegativepatients.
worsenjaundiceinpatientswithcirrhosisdueto
competitiveexcretoryinhibition.
IncreasedriskofDILI.

HepatitisBantivirals Minorornohepaticmetabolism. NodoseadjustmentnecessaryinCLDorcirrhosis.

(adefovir,entecavir, PKunalteredinCLD. Dosereductionsneededforrenalimpairment.
lamivudine,tenofovir) Safelyusedindecompensatedcirrhosiswhen
treatmentindicated.

HIVantiretrovirals ManagementofHIVantiretroviraltherapyinpatientswithhepaticimpairmentisreviewedseparately.Referto
UpToDatetopicondosemodificationofantiretroviralagentsinadultswithrenalorhepaticdysfunctionand
separatetableinUpToDateonantiretroviraldosingrecommendationsinpatientswithrenalorhepatic
insufficiency.

Antidiabetic

Insulins Insulinsarefrequentlyusedfortreatmentofdiabetes Insulinsaredosedbaseduponeffectwithcloseblood

withCLD. glucosemonitoring.
 Metformin UsedsafelyinadvancedCLDandcompensated
cirrhosis.
Beneficialintreatmentofdiabeteswithvariousforms
ofCLDincludingNAFLD.
Sulfonylureasand Sulfonylureas(eg,glipizide)arefrequentlyprescribed
meglitinides topatientswithdiabetesandCLD.
Sulfonylureasandmeglitinides(eg,repaglinide,
nateglinide)arehepaticallymetabolized,andincreased
concentrationsincirrhosisareexpected,butspecific
dataarelacking.
Cardiovascular
Antiarrhythmics Hepaticimpairmentdecreasestheeliminationofmany
antiarrhythmics.
Amiodarone Amiodaroneishighlytissueandproteinbound,
undergoesextensivehepaticmetabolismbyvarious
CYPsincluding3A4and2C8,andisexcretedfecally
viabile.
Itsextremelylonghalflifeof25to100daysis
expectedtobefurtherprolongedinhepatic
impairment.
Antihypertensives
ACEinhibitors ACEinhibitorsaregenerallywelltolerated.
MinorPKdifferencesincirrhosisincludeincreased
drugbioavailability(ie,lisinopril)orslowed
conversiontoactivedrugform(ie,enalapril),butdo
nottranslatetoamarkedlyalteredresponse.
ACEinhibitorsdonotadequatelydecreaseportal
venouspressuretoprotectagainstvaricealbleeding.
Betablockers PKcharacteristicsandmetabolismofindividualbeta
blockersvary.
Propranololandmetoprololhaveincreasedoral
bioavailabilityinadvancedCLDandcirrhosisdueto
highfirstpassextractionandproteinbinding.
CarvedilolisextensivelymetabolizedbyCYP,whereas
nadololandsotalolarenot.
Decreasedtherapeuticeffectofbetaadrenergic
blockadetherapymaybeobservedinsettingof
advancedCLDanddecompensatedcirrhosis.
Labetalolusehasbeenassociatedwithhepatoxicity.
Calciumchannel Diltiazemoralbioavailabilityisincreased,andhalflife
blockers oforalandIVareprolongedbyupto50%.
Oralbioavailabilityofverapamilisdoubled,andhalf
lifeoforalandIVareprolongedbyfourfold.
Amlodipineishighlyproteinboundandundergoes
extensivehepaticmetabolismviaCYP3A4.Halflifeis
expectedtobeprolonged(56hours)inhepatic
impairment.
Diuretics
Furosemide, Reducednatriureticpotencydependingondisease
torsemide, severity.
bumetanide Increasedsensitivitytohypokalemiaandvolume
depletion.
Spironolactone
Ingeneral,agoodchoiceformostdiabeticpatients
withmildtomoderateCLDandcompensated
cirrhosis.
Dosemetforminbasedonresponse.
Metforminshouldbeavoidedinpatientswhoconsume
excessivealcoholorwithrenalinsufficiencyor
advancedCLDorcirrhosisduetoriskoflactic
acidosis,ararebutpotentiallyfatalcomplicationof
metformintreatment.
Sulfonylureasandmeglitinidesaregenerallysafein
mildtomoderateCLDandcompensatedcirrhosis
usinglowestinitialdose,gradualtitrationbasedon
closemonitoring,andareducedmaintenancedose.
Lowdosegliclazide(notavailableinUnitedStates),
repaglinide,andnateglinidemaybereasonable
choicesduetoshorterdurationofactionandlessrisk
ofhypoglycemiaobservedingeneraldiabetic
population.
Sulfonylureasshouldbeavoidedorusedcautiouslyin
olderadultswithcirrhosisandinpatientswithrenal
insufficiencyandadvancedcirrhosis.
Dosereductionsareusuallyrequired.
RefertoLexicompindividualdrugmonographs.
Dosereductionisexpectedtobenecessaryinhepatic
impairmentandcirrhosis.
Nospecificrecommendationisavailable.
NodoseadjustmentofACEinhibitorsrequiredin
advancedCLDorcompensatedcirrhosis.
Nonprodrugs(eg,lisinopril)preferredtoprodrugs
(eg,quinapril,enalapril).
Ifcombinedwithdiuretic,usecautiouslyandin
reduceddoses.
ConsiderdiscontinuingACEinhibitorsinpatientswho
developdiureticresistantascites.RefertoUpToDate
topicreviewsofmanagingascites.
Startatlowdoseandtitratebaseduponclinical
response.
Carvediloldoseshouldbereducedbyupto80%.
Nadololandsotalolarenothepaticallymetabolized.
Doseadjustmentneededforrenalimpairment.
Nadololandpropranololcanbeusedfortreatmentof
portalhypertensionandthepreventionofvariceal
hemorrhage.RefertoUpToDatetopicreviewsof
prophylaxisagainstvaricealhemorrhage.
Discontinuationofbetablockersmaybenecessaryin
patientswhodevelopdiureticresistantascites.Refer
toUpToDatetopicreviewsofmanagingascites.
Labetalolisgenerallyavoidedintreatmentofpatients
withcirrhosis.
Startoraldiltiazematlowdoseandtitrategradually
basedonresponse.
Reduceverapamildosebyapproximately50%.
Initiateamlodipineatlowestdose(eg,2.5to5mg)
andtitrateatintervalsofnolessthan10to14days
baseduponresponse.
Furosemideisusuallygivenorallyandgradually
titratedtoeffect.
Combinationoffurosemidewithspironolactonecan
mitigateloopdiureticassociatedhypokalemiaand
improvediuresisintreatmentofascites.
RefertoUpToDatetopiconinitialtherapyofascitesin
adultswithcirrhosis.
 Extensivelymetabolizedinliver.
Severalactivemetaboliteswithprolongedhalflifein
cirrhosispermitoncedailydosingand,insome
patients,alternatedaydosing.
Incombinationwithfurosemide,counteracts
hypokalemiaandimprovesdiuresisintreatmentof
ascites.
Triamterene Triamtereneclearancedecreased.
Diureticeffectrelativelyunchangedincompensated
disease.
Nitrates MostnitratesundergononCYPhepaticand
extrahepaticmetabolism.
Orallyadministeredisosorbidedinitrateundergoes
firstpasshepaticextractionbioavailabilitymaybe
increasedinadvancedCLDorcirrhosis.
PatientswithadvancedCLDorcirrhosismayhavea
morepronouncedresponsetonitrates,including
nitrateassociatedadverseeffects(eg,hypotension,
bradycardia).
Ranolazine RanolazineundergoescomplexhepaticCYP3Aand
extrahepaticmetabolismconcentrationsare
significantlyelevatedinmoderatetoseverehepatic
impairment.
Patientswithcirrhosis,particularlyifthereisaTIPS
orsurgicalshuntpresent,maybeatelevatedriskof
developingpotentiallyfatalventriculararrhythmiasdue
toQTprolongation.
Statins Statinsaregenerallywelltoleratedinpatientswith
compensatedcirrhosisandhaveestablishedCVD
benefitsintreatmentofpatientswithNAFLD,viral
hepatitis,andprimarybiliarycirrhosis.
Moststatinsaresubjecttohighfirstpassextraction
and/orarehighlyboundtoplasmaproteins,which
canincreasebloodconcentrationsinpatientswith
hepaticimpairment.
PravastatindoesnotundergoCYPmetabolismits
clearanceislargelydependentuponrenalfunction.
Safetydataarereassuringamongpravastatintreated
patientswithcompensatednoncholestaticCLD.
Apronouncedhypolipidemicresponseinrelationto
dosemaybeevidenceofstatinaccumulation.
Gastrointestinal
Protonpumpinhibitors Protonpumpinhibitorsappeartobeapotentialrisk
factorforSBP,C.difficile,andotherseriousinfections
inpatientswithcirrhosis.
Protonpumpinhibitorsappeartobeapotentialrisk
factorforhepaticencephalopathy.
Herbalmedicinesandsupplements
Avarietyofherbalmedicinesandsupplementsmaybe
usedbypatientswithcirrhosis(eg,silymarin[milk
thistle]).
Herbsandsupplementsmaycontainundisclosed
ingredientsandcontaminants,includingprescription
medicationsthatmaybehepatotoxicorinteractwith
othermedications(eg,St.John'swort).
Hypnoticsandsedatives
Diazepam ExtensivemetabolisminliverbyCYPtoactive
metabolites.
Clearancedecreasedby50%.
Halflifeofdrugandactivemetabolitesprolongedtwo
tofivefold(ie,upto500hours).
Lorazepam Undergoesmetabolismbyglucuronidation,whichis
relativelypreservedinmildtomoderatehepatic
insufficiency.
Spironolactone100mgperdayincombinationwith
oralfurosemide40mgperdayissuggestedforinitial
treatmentofascites.
Spironolactoneandfurosemidearetitratedgradually
baseduponresponseusingaratioof100mg
spironolactoneto40mgfurosemide.
RefertoUpToDatetopiconinitialtherapyofascitesin
adultswithcirrhosis.
Lowerstartingdosesandlessfrequentdosing
dependingonseverityofCLD.
Nospecificdoseadjustmentavailable.
Doseshouldbetitratedbaseduponclinicalresponse.
Useofranolazineinpatientswithcirrhosisandany
degreeofhepaticimpairmentiscontraindicated
accordingtothelicensedproductinformation.
Initiatestatintreatmentatlowestdailydose(eg,
pravastatin10mg)andtitrategraduallybasedupon
hypolipidemicresponse.
Whilenolongerrecommendedinthegeneral
population,ALTmonitoringisreasonableforstatin
treatmentofpatientswithcirrhosis.
Avoidstatinswithdecompensateddiseaseor
significantcholestasis.
RefertoUpToDatetopicreviewofstatinactions,side
effects,andadministration.
Acidsuppressivemedicationsshouldonlybegivento
patientswhohaveclearindicationsfortheiruse.
RefertoUpToDatetopicsonoverviewoftheuseof
protonpumpinhibitorsforthetreatmentofacid
relateddisordersandontreatmentandprophylaxisof
spontaneousbacterialperitonitis.
Itisimportantforthecliniciantoaskpatientswith
CLDorcirrhosisaboutherbalmedicinesand
supplements.
Forinformationonsilymarin(milkthistle),referto
UpToDatetopicreviewofinvestigationaltherapiesfor
hepatitisCvirusinfection.
AdditionalinformationisfoundinUpToDatetopic
reviewofhepatoxicityduetoherbalmedicationsand
supplements.
Noadjustmentneededforinitialdose.
Riskofaccumulationandoversedationwithrepeated
doses.
Reducemaintenancedoseandfrequencybyupto
50%orconsideranothersedativeoption.
Prolongedeffectmightbeusefulforpatientsbeing
treatedforalcoholwithdrawalorseizures.
AvoidinpatientswithHE.
Generallyagoodchoicewhenbenzodiazepine
treatmentindicated.
Nospecificdoseadjustmenttitrategraduallydueto
prolongedonset.
 Withprolongeduseoruseasacontinuousinfusion
riskofdrugaccumulationandoversedation.
AvoidinpatientswithHE.

Midazolam ExtensivelymetabolizedintheliverbyCYP3A4and, Oralpreparationshouldbeavoidedinpatientswith

whenadministeredorally,undergoesfirstpasshepatic
extraction.
Halflifeofdrugandactivemetaboliteareincreasedin
hepaticimpairment.
advancedCLDorcirrhosisduetounpredictable
bioavailability.
ForIVuse,nospecificdoseadjustmentonce
adequatelysedatedusingsmallincrementaldoses,a
reducedmaintenancedoseandfrequencymaybe
neededtoavoidaccumulationandoversedationof
patientswithadvancedCLDorcirrhosis.
AvoidinpatientswithHE.

Zolpidem Halflifeprolongedtwofoldinmoderatehepatic Uselowestpossibledoseinpatientswithmildto

impairmentandfourfoldormoreinadvancedCLD. moderatehepaticimpairment.
Immediatereleasepreparationmaybebrokento
provide2.5mgdose.
AvoiduseinadvancedCLDmayprecipitateorworsen
HE.

Opioidusedisorder(opioidaddiction)treatment

Buprenorphinenaloxone Buccallyandsublinguallyadministerednaloxone, Buprenorphinenaloxonecombinationisnot

whichisincludedinthiscombinationtodeterabuse recommendedinpatientswithadvancedCLDor
(ie,crushing,snorting,injecting),issystemically cirrhosisduetoincreasedbioavailabilityofnaloxone.
absorbedinpatientswithmoderatetoseverehepatic
impairment.
Absorptionofnaloxonecanreverseeffectof
buprenorphineandprecipitateanopioidwithdrawal
syndrome.

Thisisnotacompletelistofcautionaryinformationanddoseadjustmentsforuseofmedicationsbypatientswithhepaticimpairment.Referto
theLexicompindividualdrugmonographsincludedwithUpToDateforadditionalinformation.Patientswithcirrhosisseemtobeatincreasedrisk
ofadverseoutcomesduetodrugdruginteractionsanddrugsthatcauseQTcprolongation,particularlyinthesettingofadvancedor
decompensateddiseaseandinthosewhohaveundergoneTIPSorsurgicalshunts.RefertotopiconacquiredlongQTsyndromefordetails.
SeparatecalculatorsareavailableinUpToDatefordeterminationofChildPughclassificationforseverityofcirrhosisbaseduponpatientclinical
andlaboratorydata(conventionalorSIunits).
Mostdrugsusedinthetreatmentoffrequentlyencounteredchronicdiseasesandinfectionscanbeusedsafelyinpatientswithchronicliver
diseaseorcompensatedcirrhosis.
Often,areduceddose,frequencyofadministration,oravoidanceofcertainmedicationsisrecommendedinthesettingofadvancedCLDor
cirrhosisbaseduponchangesindrugdisposition(eg,increasedoralbioavailability,decreasedmetabolismorproteinbinding),alteredtoxicity,
orduetoriskofprecipitatingcirrhosisassociatedcomplications(ie,avoidanceofdrugsorregimensthatcancauseGIbleeding,SBP,HE,or
renalfailure).

CLD:chronicliverdiseaseCrcl:creatinineclearanceCVD:cardiovasculardiseaseCYP:cytochromeP450DILI:druginducedliverinjuryGI:
gastrointestinalHE:hepaticencephalopathyNAFLD:nonalcoholicfattyliverdiseaseSBP:spontaneousbacterialperitonitisTIPS:transjugular
intrahepaticportosystemicshuntsVd:volumeofdistributionPK:pharmacokineticsUGT:uridine5'diphosphoglucuronosyltransferasehepatic
metabolism.
*RefertoUpToDatetopicreviewofmanagementofpaininpatientswithcirrhosisincludingaseparatetableonanalgesicsuseinadultpatientswith
advancedchronicliverdiseaseorcirrhosis.
NOTE:ThefollowingareantibioticsandantifungalsnotlistedinthetableabovethatshouldbeusedwithcautioninadvancedCLDorcirrhosis:
chloramphenicol,griseofulvin,nalidixicacid,nitrofurantoin(chronicuse),andtelithromycin.

Preparedwithdatafrom:
1.LewisJH,StineJG.Reviewarticle:Prescribingmedicationsinpatientswithcirrhosisapracticalguide.AlimentPharmacolTher201337:1132.
2.VerbeeckRK.Pharmacokineticsanddosageadjustmentinpatientswithhepaticdysfunction.EurJClinPharmacol200864:1147.
3.KlotzU.Antiarrhythmics:eliminationanddosageconsiderationsinhepaticimpairment.ClinPharmacokinet200746:985.
4.CalderonRM,CubedduLX,GoldbergRB,SchiffER.Statinsinthetreatmentofdyslipidemiainthepresenceofelevatedliveraminotransferase
levels:atherapeuticdilemma.MayoClinProc201085:349.
5.MauriCM,FiorentiniSP,AltamuraAC.Pharmacokineticsofantidepressantsinpatientswithhepaticimpairment.ClinPharmacokinet2014
53:1069.
6.TsaiCF,ChenMH,WangYP,etal.Protonpumpinhibitorsincreaseriskforhepaticencephalopathyinpatientswithcirrhosisinapopulation
study.Gastroenterology2017152:134.

Graphic90194Version9.0
Analgesicuseinadultpatientswithadvancedchronicliverdiseaseorcirrhosis
Alteredresponseandpharmacokinetics
Nonopioidanalgesics
Acetaminophen Glutathionetissuestoresneededtoblockformationof
(paracetamol) acetaminophen'stoxicmetabolite(NAPQI)arereduced
inindividualswithcirrhosisormalnutrition,thereby
loweringthedosethresholdofacetaminophenthat
canbesafelyadministeredeachday.
Activealcoholconsumptionfurtherreducesavailable
glutathionestores.
Halflifeofacetaminophenmaybeprolongedbyupto
twofoldcomparedwithhealthypatients.
Nonselective NSAIDscandecreaseGFRandimpairrenalfunctionin
nonsteroidalanti patientswithadvancedCLDorcirrhosis.
inflammatorydrugs MostNSAIDsaremetabolizedbyCYPandhighly
(NSAIDs)including boundtoserumalbumin,increasingdrug
aspirin bioavailabilityandpotentialfortoxicityinpatientswith
advancedCLDorcirrhosis.
AnincreasedriskofGImucosalbleeding,variceal
hemorrhage,impairedrenalfunction,anddevelopment
ofdiureticresistantascitesisseenwithuseofNSAIDs
inpatientswithcirrhosiswithportalhypertension.
IndividualNSAIDs(eg,diclofenac)havebeen
associatedwithhepatotoxicityingeneralpopulation.
SelectiveCOX2 Availabledataareinadequatetoestablishthesafetyof
inhibitors selectiveCOX2inhibitorsinpatientswithadvanced
CLDorcirrhosis.Seetextfordetail.
Excesscardiovasculareventshavebeenobservedwith
thisclassofmedicationswhenusedbypatients
withoutcirrhosis.
Opioidanalgesics(seeimportantnote)*
Fentanyl MetabolizedbyCYP3A4toinactive(nontoxic)
metabolites.
Parentdrugcanaccumulateafterrepeateddosingor
whenadministeredasacontinuousinfusiondueto
tissueandproteinbinding.
Lesshistaminereleasethanotheropiates.
Lesshemodynamicdisturbancethanotheropiates.
Hydrocodone, MetabolizedtoactivemetabolitebyCYP2D6and3A4
oxycodone whichmayresultinaprolongedtimetoonset,
variableanalgesicefficacy,andriskofaccumulationin
patientswithadvancedCLDorcirrhosis.
Hydromorphone HepaticallymetabolizedbynonCYPtransformations
(glucuronidation)toapparentlyinactivemetabolites.
OralbioavailabilityinadvancedCLDorcirrhosisseems
tobeincreasedrelativetohealthyindividualsdueto
diminishedfirstpassextraction,butspecificdataare
lacking,andwideinterindividualvariabilityis
observed.
Meperidine(pethidine), Alteredoralbioavailabilityandelevatedriskof
codeine accumulationofintermediates(codeine)ortoxic
metabolite(meperidine).
Managementsuggestions
Acetaminophenisgenerallywelltoleratedinpatients
withCLDorcirrhosiswhodonotconsumealcohol,
providedthetotaldailydoseislimitedtonomore
than2g/day.
Forshorttermoronetimeuse,amaximumtotal
acetaminophendoseofupto3g/daymaybe
consideredinlowerriskpatients(eg,donotconsume
alcohol)withCLDorearlystagecompensated
cirrhosis.
Warnpatientsconcerningacetaminophencontentin
combinationprescriptionanalgesics(eg,oxycodone
acetaminophen)andnonprescription(OTC)
preparations.
AvoiduseinpatientswithadvancedCLDorcirrhosis
whoareactivelyconsumingalcohol,malnourished,
noteating,receivingmultiplemedicationsthat
undergohepaticbiotransformations,oranyco
administeredmedicationthatisapotentinducerof
hepaticenzymes.
Alistofmedicationsthatinducehepaticenzymesis
providedinaseparatetable.
NSAIDsandaspirinshouldbeavoidedinpatientswith
advancedCLDorcirrhosis.
Lowdoseacetaminophenshouldbeusedinsteadof
NSAIDs.
WeadviseagainstuseofselectiveCOX2inhibitorsin
patientswithadvancedCLDorcirrhosis,pending
availabilityofadditionalsafetydata.
Ifused,celecoxibproductinformationsuggestsa
50%dosereductionforChildPughclassBcirrhosis.
GenerallyagoodchoiceforpatientswithCLDor
cirrhosiswhenopiatetreatmentindicated.
Usefuloptioninpatientswithrenalfailureinsettingof
cirrhosis.
Nodoseadjustmentneededforsingledose.
Withrepeateddosing,reducedoseandfrequencyby
approximately25to50%.
Initiatetransdermalpatchathalfusualdose.
Duetovariabilityofonsetandanalgesicefficacyin
hepaticinsufficiency,fentanylorhydromorphonemay
bebettertoleratedandmoresafelyandpredictably
adjustedthanhydrocodoneandoxycodoneinpatients
withadvancedCLDorcirrhosis.
Ifused,reducedoseandfrequency.
Generallyagoodchoiceforpatientswithadvanced
CLDorcirrhosis.
Reducedoseandfrequencybyapproximately50%.
Titratedosegraduallytoavoidaccumulationofactive
drug.
Usefuloptioninpatientswithrenalfailureinsettingof
cirrhosis.
SmallvolumeforIVpreparationandnonCYP3A4
metabolismmaybeadvantageousgivenclinical
setting.
Meperidineandcodeineshouldbeavoidedinpatients
withadvancedCLDorcirrhosis.
 Meperidineishighlyboundtoserumprotein.
Unpredictableanalgesicefficacyandincreasedriskof
toxicityinpatientswithadvancedCLDorcirrhosis.
Morphine OralbioavailabilityinadvancedCLDorcirrhosis
increasedupto100%relativetohealthyindividuals
duetodiminishedfirstpassextraction.Wideinter
individualvariabilitymaybeseen.
HepaticallymetabolizedbynonCYPtransformations
(glucuronidation).
Halflifecanbeincreasedbyuptotwofold.
Accumulationofmetaboliteswithcomplexeffects(eg,
respiratorydepression,analgesictolerance,
neurotoxicity)canoccurinpatientswithcirrhosisand
renalfailure.
Naloxonecontaining Orallyadministerednaloxone,whichisincludedin
opioidcombinations thesecombinationstodeterabuse(ie,crushing,
snorting)andcounteractconstipationbyalocal
effect,issystemicallyabsorbedinpatients
withmoderatetoseverehepaticimpairment.
Systemicabsorptionofnaloxonewillreverseanalgesic
efficacyandcanprecipitateopioidwithdrawal.
Remifentanil Clearedbynonspecificplasmaesterasestoinactive
metabolites.
Doesnotaccumulateinhepaticorrenalinsufficiency.
Promptreversalofanalgesiaandsedationupon
discontinuation.
Tramadol Hepaticallymetabolizedtoactivemetaboliteby
CYP3A4,2D6andglucuronidation.
Unpredictableonset,variableanalgesicefficacy,and
riskofaccumulationinpatientswithcirrhosis.
Caninteractwithserotoninergicmedicationsincluding
antidepressants.
Adjunctiveagentsforneuropathicpain
Carbamazepine Carbamazepineisapotentinducerofhepaticenzymes
andhasbeenassociatedwithhepatotoxicityand
seriousallergicreactionsingeneticallypredisposed
individuals.
Mayprecipitaterapiddecompensationinpatientswith
cirrhosis.
Gabapentin Nothepaticallymetabolizedorboundtoplasma
proteins.
Highlydependentuponrenalfunctionforclearanceof
unchangeddrug.
Sedation,ataxia,dizziness,andnauseamaylimit
usefulnessinpatientswithadvancedCLDorcirrhosis.
Lidocainetopicalpatch Low(3to5%)systemicabsorptionthroughintact
skin.
Nortriptyline Subjecttoextensivefirstpassmetabolismand
CYP2D6transformations,whichincludeactiveand
inactivemetabolites.
Accumulationofmetabolitesinhepaticimpairmentis
lesslikelywithnortriptylinethanamitriptyline.
Doserelatedanticholinergicandcardiovascularside
effectsmaybepoorlytoleratedinmedicallyillpatients
withadvancedCLDorcirrhosis.
Pregabalin Nothepaticallymetabolizedorboundtoplasma
proteins.
Highlydependentuponrenalfunctionforclearanceof
unchangeddrug.
Sedationanddizzinessmaylimitusefulnessinpatients
withadvancedCLDorcirrhosis.
Reducedoseandfrequencybyapproximately50%in
advancedCLDorcirrhosis.
Titratedosegraduallytoavoidaccumulationofactive
drug.
Avoidinpatientswithcirrhosisandrenalfailure.
Oxycodonenaloxone:
Reducestartingdosebyonehalftotwothirdsin
mildhepaticimpairment
UseinadvancedCLDorcirrhosisis
contraindicated
Pentazocinenaloxone:Avoiduse
Noadjustmentneeded.
Avoiduseinpatientswithdecompensatedcirrhosis.
Avoiduseinpatientsatriskforseizures.
Baseduponlimitedexperience,areduceddoseof25
mgeveryeighthoursmaybeconsideredfortreatment
ofpaininpatientswithadvancedCLDorwell
compensatedcirrhosis.
Carbamazepineshouldbeavoidedastherearesafer
optionsfortreatmentofneuropathicpaininpatients
withadvancedCLDorcirrhosis.
Initiatetreatmentat300mgorallyperdayand
graduallytitratedoseifneededoverweeksdueto
delayedonsetofactionandtoimprovetolerability.
Maintenancedoseisdependentuponrenalfunction.
Forspecificadjustment,refertoLexicompmonograph
includedwithUpToDate.
Accordingtotheproductinformation,shouldnotbe
abruptlystoppedduetoriskofdiscontinuation
symptoms(eg,nausea,insomnia,anxiety)and/or
reboundseizuresinatriskpatients.
Agoodchoiceforlocalreliefofpaininlimitedareas
ofintactskininpatientswithadvancedCLDor
cirrhosis.
Noadjustmentneededinhepaticimpairment.
Initiatetreatmentat10mgorallyeachnightand
graduallytitratedoseifneededoverweeksdueto
delayedonsetofactionandtoimprovetolerability.
Use"low"maintenancedoseforneuropathicpain(eg,
25mgtonomorethan50mgdaily)todecreaserisk
ofaccumulation.
Initiatetreatmentat50mgorallytwiceperdayand
graduallytitratedoseifneededoverweeksdueto
delayedonsetofaction.
Maintenancedoseisdependentuponrenalfunction.
Forspecificadjustment,refertoLexicompmonograph
includedwithUpToDate.
Accordingtotheproductinformation,shouldnotbe
abruptlystoppedduetoriskofdiscontinuation
symptoms(eg,nausea,insomnia,anxiety)and/or
reboundseizuresinatriskpatients.
Forinformationaboutuseandadjustmentofmedicationsotherthananalgesicsinchronicliverdisease,refertoseparatetableinUpToDateon
nonanalgesicmedicationsusedinadultpatientswithadvancedchronicliverdiseaseorcirrhosis.

OTC:overthecounteranalgesicCOX2:cyclooxygenase2CLD:chronicliverdiseaseCYP:cytochromeP450NSAID:nonsteroidalantiinflammatory
drugNAPQI:nacetylpbenzoquinoneimineHE:hepaticencephalopathy.
*NOTE:AllopioidscanworsenorprecipitateHEandshouldbeusedcautiouslyoravoidedinpatientswithportalhypertensionandpreexistingHE.

Preparedwithdatafrom:
1.LewisJH,StineJG.Reviewarticle:Prescribingmedicationsinpatientswithcirrhosisapracticalguide.AlimentPharmacolTher201337:1132.
2.ChandokN,WattKD.Painmanagementinthecirrhoticpatient:Theclinicalchallenge.MayoClinProc201085(5):451.

Graphic90196Version11.0
VaccinesthatmightbeindicatedforadultsbasedonmedicalandotherindicationsUnitedStates,2017

*Influenzavaccination:
Generalinformation
Allpersonsaged6monthsorolderwhodonothaveacontraindicationshouldreceiveannualinfluenzavaccinationwithanageappropriateformulationofina
recombinantinfluenzavaccine(RIV).
InadditiontostandarddoseIIV,availableoptionsforadultsinspecificagegroupsincludehighdoseoradjuvantedIIVforadultsaged65yearsorolder,int
64years,andRIVforadultsaged18yearsorolder.
Notes:Liveattenuatedinfluenzavaccine(LAIV)shouldnotbeusedduringthe2016to2017influenzaseason.Alistofcurrentlyavailableinfluenzavaccinesis
www.cdc.gov/flu/protect/vaccine/vaccines.htm.
Specialpopulations
AdultswithahistoryofeggallergywhohaveonlyhivesafterexposuretoeggshouldreceiveageappropriateIIVorRIV.
Adultswithahistoryofeggallergyotherthanhives(eg,angioedema,respiratorydistress,lightheadedness,orrecurrentemesis)orwhorequiredepinephrine
interventionmayreceiveageappropriateIIVorRIV.Theselectedvaccineshouldbeadministeredinaninpatientoroutpatientmedicalsettingandunderthes
abletorecognizeandmanagesevereallergicconditions.
PregnantwomenandwomenwhomightbecomepregnantintheupcominginfluenzaseasonshouldreceiveIIV.
Tetanus,diphtheria,andacellularpertussisvaccination:
Generalinformation
Adultswhohavenotreceivedtetanusanddiphtheriatoxoidsandacellularpertussisvaccine(Tdap)orforwhompertussisvaccinationstatusisunknownshou
tetanusanddiphtheriatoxoids(Td)boosterevery10years.Tdapshouldbeadministeredregardlessofwhenatetanusordiphtheriatoxoidcontainingvaccine
Adultswithanunknownorincompletehistoryofa3doseprimaryserieswithtetanusanddiphtheriatoxoidcontainingvaccinesshouldcompletetheprimary
Unvaccinatedadultsshouldreceivethefirst2dosesatleast4weeksapartandthethirddose6to12monthsaftertheseconddose.
Notes:InformationontheuseofTdorTdapastetanusprophylaxisinwoundmanagementisavailableatwww.cdc.gov/mmwr/preview/mmwrhtml/rr5517a1.h
Specialpopulations
Pregnantwomenshouldreceive1doseofTdapduringeachpregnancy,preferablyduringtheearlypartofgestationalweeks27to36,regardlessofpriorhist
Measles,mumps,andrubellavaccination:
Generalinformation
Adultsbornin1957orlaterwithoutacceptableevidenceofimmunitytomeasles,mumps,orrubella(definedbelow)shouldreceive1doseofmeasles,mumps
haveamedicalcontraindicationtothevaccine(eg,pregnancyorsevereimmunodeficiency).
Notes:Acceptableevidenceofimmunitytomeasles,mumps,orrubellainadultsisbornbefore1957,documentationofreceiptofMMR,orlaboratoryevidence
ofhealthcareproviderdiagnoseddiseasewithoutlaboratoryconfirmationisnotacceptableevidenceofimmunity.
Specialpopulations
Pregnantwomenwhodonothaveevidenceofimmunitytorubellashouldreceive1doseofMMRuponcompletionorterminationofpregnancyandbeforedisc
pregnantwomenofchildbearingagewithoutevidenceofrubellaimmunityshouldreceive1doseofMMR.
Adultswithprimaryoracquiredimmunodeficiencyincludingmalignantconditionsaffectingthebonemarroworlymphaticsystem,systemicimmunosuppressiv
shouldnotreceiveMMR.
Adultswithhumanimmunodeficiencyvirus(HIV)infectionandCD4+Tlymphocytecount200cells/mcLforatleast6monthswhodonothaveevidenceofm
shouldreceive2dosesofMMRatleast28daysapart.AdultswithHIVinfectionandCD4+Tlymphocytecount<200cells/mcLshouldnotreceiveMMR.
 Adultswhoworkinhealthcarefacilitiesshouldreceive2dosesofMMRatleast28daysaparthealthcarepersonnelbornbefore1957whoareunvaccinatedor
mumps,orrubellaimmunity,orlaboratoryconfirmationofdiseaseshouldbeconsideredforvaccinationwith2dosesofMMRatleast28daysapartformeasle
rubella.
Adultswhoarestudentsinpostsecondaryeducationalinstitutionsorplantotravelinternationallyshouldreceive2dosesofMMRatleast28daysapart.
Adultswhoreceivedinactivated(killed)measlesvaccineormeaslesvaccineofunknowntypeduringyears1963to1967shouldberevaccinatedwith1or2do
Adultswhowerevaccinatedbefore1979witheitherinactivatedmumpsvaccineormumpsvaccineofunknowntypewhoareathighriskformumpsinfection,
beconsideredforrevaccinationwith2dosesofMMRatleast28daysapart.
Varicellavaccination:
Generalinformation
Adultswithoutevidenceofimmunitytovaricella(definedbelow)shouldreceive2dosesofsingleantigenvaricellavaccine(VAR)4to8weeksapart,oraseco
PersonswithoutevidenceofimmunityforwhomVARshouldbeemphasizedareadultswhohaveclosecontactwithpersonsathighriskforseriouscomplicati
householdcontactsofimmunocompromisedpersons),adultswholiveorworkinanenvironmentinwhichtransmissionofvaricellazostervirusislikely(eg,t
andstaffininstitutionalsettings),adultswholiveorworkinenvironmentsinwhichvaricellatransmissionhasbeenreported(eg,collegestudents,residentsa
institutions,andmilitarypersonnel),nonpregnantwomenofchildbearingage,adolescentsandadultslivinginhouseholdswithchildren,andinternationaltra
Notes:EvidenceofimmunitytovaricellainadultsisUnitedStatesbornbefore1980(forpregnantwomenandhealthcarepersonnel,UnitedStatesbornbefore
immunity),documentationof2dosesofVARatleast4weeksapart,historyofvaricellaorherpeszosterdiagnosisorverificationofvaricellaorherpeszoster
laboratoryevidenceofimmunityordisease.
Specialpopulations
Pregnantwomenshouldbeassessedforevidenceofvaricellaimmunity.Pregnantwomenwhodonothaveevidenceofimmunityshouldreceivethefirstdose
pregnancyandbeforedischargefromthehealthcarefacility,andtheseconddose4to8weeksafterthefirstdose.
Healthcareinstitutionsshouldassessandensurethatallhealthcarepersonnelhaveevidenceofimmunitytovaricella.
Adultswithmalignantconditions,includingthosethataffectthebonemarroworlymphaticsystemorwhoreceivesystemicimmunosuppressivetherapy,shou
Adultswithhumanimmunodeficiencyvirus(HIV)infectionandCD4+Tlymphocytecount200cells/mcLmayreceive2dosesofVAR3monthsapart.Adults
lymphocytecount<200cells/mcLshouldnotreceiveVAR.
Herpeszostervaccination:
Generalinformation
Adultsaged60yearsoroldershouldreceive1doseofherpeszostervaccine(HZV),regardlessofwhethertheyhadapriorepisodeofherpeszoster.
Specialpopulations
Adultsaged60yearsorolderwithchronicmedicalconditionsmayreceiveHZVunlesstheyhaveamedicalcontraindication(eg,pregnancyorsevereimmunod
Adultswithmalignantconditions,includingthosethataffectthebonemarroworlymphaticsystemorwhoreceivesystemicimmunosuppressivetherapy,shou
AdultswithhumanimmunodeficiencyvirusinfectionandCD4+Tlymphocytecount<200cells/mcLshouldnotreceiveHZV.
Humanpapillomavirusvaccination:
Generalinformation
Adultfemalesthroughage26yearsandadultmalesthroughage21yearswhohavenotreceivedanyhumanpapillomavirus(HPV)vaccineshouldreceivea3d
and6months.Malesaged22through26yearsmaybevaccinatedwitha3doseseriesofHPVvaccineat0,1to2,and6months.
Adultfemalesthroughage26yearsandadultmalesthroughage21years(andmalesaged22through26yearswhomayreceiveHPVvaccination)whoinitiate
15yearsandreceived2dosesatleast5monthsapartareconsideredadequatelyvaccinatedanddonotneedanadditionaldoseofHPVvaccine.
Adultfemalesthroughage26yearsandadultmalesthroughage21years(andmalesaged22through26yearswhomayreceiveHPVvaccination)whoinitiate
15yearsandreceivedonly1dose,or2doseslessthan5monthsapart,arenotconsideredadequatelyvaccinatedandshouldreceive1additionaldoseofHPV
Notes:HPVvaccinationisroutinelyrecommendedforchildrenatage11or12years.ForadultswhohadinitiatedbutdidnotcompletetheHPVvaccinationser
vaccination(describedabove)andotherfactors(describedbelow)todetermineiftheyhavebeenadequatelyvaccinated.
Specialpopulations
Menwhohavesexwithmenthroughage26yearswhohavenotreceivedanyHPVvaccineshouldreceivea3doseseriesofHPVvaccineat0,1to2,and6m
Adultfemalesandmalesthroughage26yearswithimmunocompromisingconditions(describedbelow),includingthosewithhumanimmunodeficiencyvirusi
HPVvaccineat0,1to2,and6months.
PregnantwomenarenotrecommendedtoreceiveHPVvaccine,althoughthereisnoevidencethatthevaccineposesharm.Ifawomanisfoundtobepregnan
delaytheremainingdosesuntilafterthepregnancy.Nootherinterventionisneeded.PregnancytestingisnotneededbeforeadministeringHPVvaccine.
Notes:Immunocompromisingconditionsforwhicha3doseseriesofHPVvaccineisindicatedareprimaryorsecondaryimmunocompromisingconditionstha
immunity(eg,Blymphocyteantibodydeficiencies,completeorpartialTlymphocytedefects,HIVinfection,malignantneoplasm,transplantation,autoimmuned
Pneumococcalvaccination:
Generalinformation
Adultswhoareimmunocompetentandaged65yearsoroldershouldreceive13valentpneumococcalconjugatevaccine(PCV13)followedby23valentpneum
atleast1yearafterPCV13.
Notes:Adultsarerecommendedtoreceive1doseofPCV13and1,2,or3dosesofPPSV23dependingonindication.WhenbothPCV13andPPSV23areindic
PCV13andPPSV23shouldnotbeadministeredduringthesamevisit.IfPPSV23haspreviouslybeenadministered,PCV13shouldbeadministeredatleast1ye
dosesofPPSV23areindicated,theintervalbetweenPPSV23dosesshouldbeatleast5years.Supplementalinformationonpneumococcalvaccinetimingfora
aged19yearsorolderathighriskforpneumococcaldisease(describedbelow)isavailableathttps://www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo
ofPPSV23areindicatedforadultswhoreceivedPPSV23atage65yearsorolder.Whenindicated,PCV13andPPSV23shouldbeadministeredtoadultswhose
incompleteorunknown.
Specialpopulations
Adultsaged19through64yearswithchronicheartdiseaseincludingcongestiveheartfailureandcardiomyopathies(excludinghypertension)chroniclungdi
disease,emphysema,andasthmachronicliverdiseaseincludingcirrhosisalcoholismordiabetesmellitusorwhosmokecigarettesshouldreceivePPSV23.
receivePCV13andanotherdoseofPPSV23atleast1yearafterPCV13andatleast5yearsafterthemostrecentdoseofPPSV23.
Adultsaged19yearsorolderwithimmunocompromisingconditionsoranatomicalorfunctionalasplenia(describedbelow)shouldreceivePCV13andadose
followedbyaseconddoseofPPSV23atleast5yearsafterthefirstdoseofPPSV23.IfthemostrecentdoseofPPSV23wasadministeredbeforeage65years
anotherdoseofPPSV23atleast8weeksafterPCV13andatleast5yearsafterthemostrecentdoseofPPSV23.
Adultsaged19yearsorolderwithcerebrospinalfluidleakorcochlearimplantshouldreceivePCV13followedbyPPSV23atleast8weeksafterPCV13.Ifthem
administeredbeforeage65years,atage65yearsorolder,administeranotherdoseofPPSV23atleast8weeksafterPCV13andatleast5yearsafterthemos
Notes:ImmunocompromisingconditionsthatareindicationsforpneumococcalvaccinationarecongenitaloracquiredimmunodeficiencyincludingBorTlym
deficiencies,andphagocyticdisordersexcludingchronicgranulomatousdiseasehumanimmunodeficiencyvirusinfectionchronicrenalfailureandnephrotic
disease,generalizedmalignancy,andmultiplemyelomasolidorgantransplantandiatrogenicimmunosuppressionincludinglongtermsystemiccorticosteroid
functionalaspleniathatareindicationsforpneumococcalvaccinationaresicklecelldiseaseandotherhemoglobinopathies,congenitaloracquiredasplenia,spl
Pneumococcalvaccinesshouldbegivenatleast2weeksbeforeimmunosuppressivetherapyoranelectivesplenectomy,andassoonaspossibletoadultswho
HepatitisAvaccination:
Generalinformation
AdultswhoseekprotectionfromhepatitisAvirusinfectionmayreceivea2doseseriesofsingleantigenhepatitisAvaccine(HepA)ateither0and6to12mon
(Vaqta).AdultsmayalsoreceiveacombinedhepatitisAandhepatitisBvaccine(HepAHepBTwinrix)asa3doseseriesat0,1,and6months.Acknowledgme
seekprotectionisnotneeded.
Specialpopulations
AdultswithanyofthefollowingindicationsshouldreceiveaHepAseries:havechronicliverdisease,receiveclottingfactorconcentrates,menwhohavesexw
drugs,orworkwithhepatitisAvirusinfectedprimatesorinahepatitisAresearchlaboratorysetting.
 AdultswhotravelincountrieswithhighorintermediatelevelsofendemichepatitisAinfectionoranticipateclosepersonalcontactwithaninternationaladopte
regularlybabysit)fromacountrywithhighorintermediatelevelofendemichepatitisAinfectionwithinthefirst60daysofarrivalintheUnitedStatesshouldr
**HepatitisBvaccination:
Generalinformation
AdultswhoseekprotectionfromhepatitisBvirusinfectionmayreceivea3doseseriesofsingleantigenhepatitisBvaccine(HepBEngerixB,RecombivaxHB)
receiveacombinedhepatitisAandhepatitisBvaccine(HepAHepBTwinrix)at0,1,and6months.Acknowledgmentofaspecificriskfactorbythosewhosee
Specialpopulations
AdultsatriskforhepatitisBvirusinfectionbysexualexposureshouldreceiveaHepBseries,includingsexpartnersofhepatitisBsurfaceantigen(HBsAg)pos
arenotinamutuallymonogamousrelationship,personsseekingevaluationortreatmentforasexuallytransmittedinfection,andmenwhohavesexwithmen
AdultsatriskforhepatitisBvirusinfectionbypercutaneousormucosalexposuretobloodshouldreceiveaHepBseries,includingadultswhoarerecentorcu
contactsofHBsAgpositivepersons,residentsandstaffoffacilitiesfordevelopmentallydisabledpersons,incarcerated,healthcareandpublicsafetyworkersat
contaminatedbodyfluids,youngerthanage60yearswithdiabetesmellitus,andage60yearsorolderwithdiabetesmellitusatthediscretionofthetreatingc
Adultswithchronicliverdiseaseincluding,butnotlimitedto,hepatitisCvirusinfection,cirrhosis,fattyliverdisease,alcoholicliverdisease,autoimmunehepa
(ALT)oraspartateaminotransferase(AST)levelgreaterthantwicetheupperlimitofnormalshouldreceiveaHepBseries.
Adultswithendstagerenaldiseaseincludingthoseonpredialysiscare,hemodialysis,peritonealdialysis,andhomedialysisshouldreceiveaHepBseries.Adu
doseseriesof40mcgRecombivaxHBat0,1,and6monthsora4doseseriesof40mcgEngerixBat0,1,2,and6months.
AdultswithhumanimmunodeficiencyvirusinfectionshouldreceiveaHepBseries.
PregnantwomenwhoareatriskforhepatitisBvirusinfectionduringpregnancy(eg,havingmorethanonesexpartnerduringtheprevioussixmonths,been
transmittedinfection,recentorcurrentinjectiondruguse,orhadanHBsAgpositivesexpartner)shouldreceiveaHepBseries.
InternationaltravelerstoregionswithhighorintermediatelevelsofendemichepatitisBvirusinfectionshouldreceiveaHepBseries.
AdultsinthefollowingsettingsareassumedtobeatriskforhepatitisBvirusinfectionandshouldreceiveaHepBseries:sexuallytransmitteddiseasetreatmen
facilities,facilitiesprovidingdrugabusetreatmentandpreventionservices,healthcaresettingstargetingservicestopersonswhoinjectdrugs,correctionalfac
servicestoMSM,hemodialysisfacilitiesandendstagerenaldiseaseprograms,andinstitutionsandnonresidentialdaycarefacilitiesfordevelopmentallydisabl
Meningococcalvaccination:
Specialpopulations
Adultswithanatomicalorfunctionalaspleniaorpersistentcomplementcomponentdeficienciesshouldreceivea2doseprimaryseriesofserogroupsA,C,W,
(MenACWY)atleast2monthsapartandrevaccinateevery5years.TheyshouldalsoreceiveaseriesofserogroupBmeningococcalvaccine(MenB)witheither
least1monthapartora3doseseriesofMenBFHbp(Trumenba)at0,1to2,and6months.
Adultswithhumanimmunodeficiencyvirusinfectionwhohavenotbeenpreviouslyvaccinatedshouldreceivea2doseprimaryseriesofMenACWYatleast2m
Thosewhopreviouslyreceived1doseofMenACWYshouldreceiveaseconddoseatleast2monthsafterthefirstdose.AdultswithHIVinfectionarenotrouti
becausemeningococcaldiseaseinthispopulationiscausedprimarilybyserogroupsC,W,andY.
MicrobiologistswhoareroutinelyexposedtoisolatesofNeisseriameningitidisshouldreceive1doseofMenACWYandrevaccinateevery5yearsiftheriskfor
seriesofMenB4Catleast1monthapartora3doseseriesofMenBFHbpat0,1to2,and6months.
Adultsatriskbecauseofameningococcaldiseaseoutbreakshouldreceive1doseofMenACWYiftheoutbreakisattributabletoserogroupA,C,W,orY,orei
monthapartora3doseseriesofMenBFHbpat0,1to2,and6monthsiftheoutbreakisattributabletoserogroupB.
Adultswhotraveltoorliveincountrieswithhyperendemicorepidemicmeningococcaldiseaseshouldreceive1doseofMenACWYandrevaccinateevery5yea
isnotroutinelyindicatedbecausemeningococcaldiseaseinthesecountriesisgenerallynotcausedbyserogroupB.
Militaryrecruitsshouldreceive1doseofMenACWYandrevaccinateevery5yearsiftheincreasedriskforinfectionremains.
Firstyearcollegestudentsaged21yearsoryoungerwholiveinresidencehallsshouldreceive1doseofMenACWYiftheyhavenotreceivedMenACWYatage
Youngadultsaged16through23years(preferredagerangeis16through18years)whoarehealthyandnotatincreasedriskforserogroupBmeningococc
eithera2doseseriesofMenB4Catleast1monthapartora2doseseriesofMenBFHbpat0and6monthsforshorttermprotectionagainstmoststrainso
Foradultsaged56yearsorolderwhohavenotpreviouslyreceivedserogroupsA,C,W,andYmeningococcalvaccineandneedonly1dose,meningococcalp
vaccine(MPSV4)ispreferred.ForadultswhopreviouslyreceivedMenACWYoranticipatereceivingmultipledosesofserogroupsA,C,W,andYmeningococca
Notes:MenB4CandMenBFHbparenotinterchangeable(ie,thesamevaccineshouldbeusedforalldosestocompletetheseries).Thereisnorecommendati
MenBmaybeadministeredatthesametimeasMenACWYbutatadifferentanatomicsite,iffeasible.
Haemophilusinfluenzaetypebvaccination:
Specialpopulations
Adultswhohaveanatomicalorfunctionalaspleniaorsicklecelldisease,orareundergoingelectivesplenectomyshouldreceive1doseofH.influenzae
previouslyreceivedHib.Hibshouldbeadministeredatleast14daysbeforesplenectomy.
Adultswithahematopoieticstemcelltransplant(HSCT)shouldreceive3dosesofHibinatleast4weekintervals6to12monthsaftertransplantregardlesso
Notes:HibisnotroutinelyrecommendedforadultswithhumanimmunodeficiencyvirusinfectionbecausetheirriskforHaemophilusinfluenzaetypebinfectio

Reproducedfrom:AdvisoryCommitteeonImmunizationPractices(ACIP).AdvisoryCommitteeonImmunizationPracticesRecommendedImmunizationSchedulefor
States,2017.Availableat:http://www.cdc.gov/vaccines/schedules/downloads/adult/adultcombinedschedule.pdf(AccessedonFebruary8,2017).

Graphic62130Version14.0
Precipitantsofhepaticencephalopathyinpatientswithcirrhosis

Drugs
Benzodiazepines

Nonbenzodiazepinehypnotics(eg,zolpidem)

Narcotics

Alcohol

Increasedammoniaproduction,absorptionorentryintothebrain
Excessdietaryintakeofprotein

Gastrointestinalbleeding

Infection

Electrolytedisturbancessuchashypokalemia

Constipation

Metabolicalkalosis

Dehydration
Vomiting

Diarrhea

Hemorrhage

Diuretics

Largevolumeparacentesis

Portosystemicshunting
Radiographicorsurgicallyplacedshunts

Spontaneousshunts

Vascularocclusion
Hepaticveinthrombosis

Portalveinthrombosis

Primaryhepatocellularcarcinoma

Graphic50440Version4.0
ChildPughclassificationofseverityofcirrhosis

Pointsassigned
Parameter
1 2 3

Ascites Absent Slight Moderate

Bilirubin <2mg/dL(<34.2micromol/L) 2to3mg/dL(34.2to51.3 >3mg/dL(>51.3micromol/L)

micromol/L)

Albumin >3.5g/dL(35g/L) 2.8to3.5g/dL(28to35g/L) <2.8g/dL(<28g/L)

Prothrombintime

Secondsovercontrol <4 4to6 >6

INR <1.7 1.7to2.3 >2.3

Encephalopathy None Grade1to2 Grade3to4

ModifiedChildPughclassificationoftheseverityofliverdiseaseaccordingtothedegreeofascites,theserumconcentrationsofbilirubinand
albumin,theprothrombintime,andthedegreeofencephalopathy.AtotalChildTurcottePughscoreof5to6isconsideredChildPughclassA
(wellcompensateddisease)7to9isclassB(significantfunctionalcompromise)and10to15isclassC(decompensateddisease).Theseclasses
correlatewithoneandtwoyearpatientsurvival:classA:100and85percentclassB:80and60percentandclassC:45and35percent.

INR:internationalnormalizedratio.

Graphic78401Version11.0
ChildTurcotteclassificationofpatientswithcirrhosis

Parameter A B C

Ascites None Easilycontrolled Poorlycontrolled

Bilirubin <2mg/dL(<34.2micromol/liter) 2to3mg/dL(34.2to51.3micromol/liter) >3mg/dL(>51.3micromol/liter)

Albumin >3.5g/dL(>35g/liter) 3.0to3.5g/dL(30to35g/liter) <3.0g/dL(<30g/liter)

Encephalopathy None Mild Advanced

Nutritionalstatus Excellent Good Poor

Graphic56436Version3.0
ContributorDisclosures
EricGoldberg,MD Nothingtodisclose SanjivChopra,MD,MACP Nothingtodisclose BruceARunyon,MD Nothingto
disclose KristenMRobson,MD,MBA,FACG Consultant/AdvisoryBoards:ActavisPharmaInc.[IBSD(Eluxadoline)].

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