cirrhosis- practice essentials, overview, epidemiology

9/26/2015 Cirrhosis: Practice Essentials, Overview, Epidemiology

http://emedicine.medscape.com/article/185856-overview#a2 1/21

Cirrhosis

Author:DavidCWolf,MD,FACP,FACG,AGAF,FAASLDChiefEditor:BSAnand,MDmore...

Updated:Dec10,2014

PracticeEssentialsCirrhosisisdefinedhistologicallyasadiffusehepaticprocesscharacterizedbyfibrosisandtheconversionofnormalliverarchitectureintostructurallyabnormalnodules.Theprogressionofliverinjurytocirrhosismayoccuroverweekstoyears.

Essentialupdate:TURQUOISEIIdatasuggest3D+RBVimprovesliver

functioninhepatitisCpatientswithcirrhosis

AccordingtoananalysisofdatafromtheTURQUOISEIIstudy,presentedinOctober2014attheAnnualScientificMeetingoftheAmericanCollegeofGastroenterology(ACG),treatmentwiththecombinationoftheproteaseinhibitorABT450boostedwithritonavir,theNS5Ainhibitorombitasvir,andthenonnucleosidepolymeraseinhibitordasabuvirplusribavirin(3D+RBV)improvedmeasuresofliverfunctionat12weeksinhepatitisCpatientswithcirrhosis.[1]

Highlysignificantimprovementsfrombaselinewereseenat12weeksfortheliverenzymesalanineaminotransferase,aspartateaminotransferase,andgammaglutamyltransferase.[1]Amongpatientswithelevatedtransaminaselevelsatbaseline,levelsnormalizedafter12weeksin7090%ofcases.Highlysignificantimprovementswerealsoobservedinconjugatedbilirubinandalbuminlevelsandinprothrombintimeat12weeks.

Signsandsymptoms

Somepatientswithcirrhosisarecompletelyasymptomaticandhaveareasonablynormallifeexpectancy.Otherindividualshaveamultitudeofthemostseveresymptomsofendstageliverdiseaseandalimitedchanceforsurvival.Commonsignsandsymptomsmaystemfromdecreasedhepaticsyntheticfunction(eg,coagulopathy),portalhypertension(eg,varicealbleeding),ordecreaseddetoxificationcapabilitiesoftheliver(eg,hepaticencephalopathy).

Portalhypertension

Portalhypertensioncanhaveprehepatic,intrahepatic,orposthepaticcauses.BuddChiarisyndrome,aposthepaticcause,ischaracterizedbythefollowingsymptoms:

HepatomegalyAbdominalpainAscites

Ascitesissuggestedbythefollowingfindingsonphysicalexamination:

AbdominaldistentionBulgingflanksShiftingdullnessElicitationofa"puddlesign"inpatientsinthekneeelbowposition

Hepaticencephalopathy

Thesymptomsofhepaticencephalopathymayrangefrommildtosevereandmaybeobservedinasmanyas70%ofpatientswithcirrhosis.Symptomsaregradedonthefollowingscale:

Grade0Subclinicalnormalmentalstatusbutminimalchangesinmemory,concentration,intellectualfunction,coordinationGrade1Mildconfusion,euphoriaordepression,decreasedattention,slowingofabilitytoperformmentaltasks,irritability,disorderofsleeppattern(ie,invertedsleepcycle)Grade2Drowsiness,lethargy,grossdeficitsinabilitytoperformmentaltasks,obviouspersonalitychanges,inappropriatebehavior,intermittentdisorientation(usuallywithregardtotime)Grade3Somnolent,butarousablestateinabilitytoperformmentaltasksdisorientationwithregardtotimeandplacemarkedconfusionamnesiaoccasionalfitsofragespeechispresentbutincomprehensibleGrade4Coma,withorwithoutresponsetopainfulstimuli

Findingsonphysicalexaminationinhepaticencephalopathyincludeasterixisandfetorhepaticus.

Additionalsignsandsymptoms

Manypatientswithcirrhosisexperiencefatigue,anorexia,weightloss,andmusclewasting.Cutaneousmanifestationsofcirrhosisincludejaundice,spiderangiomata,skintelangiectasias("papermoneyskin"),palmarerythema,whitenails,disappearanceoflunulae,andfingerclubbing,especiallyinthesettingofhepatopulmonarysyndrome.

Diagnosis

Hepatorenalsyndrome

Hepatorenalsyndromeisdiagnosedwhenacreatinineclearancerateoflessthan40mL/minispresentorwhenaserumcreatininelevelofgreaterthan1.5mg/dL,a



urinevolumeoflessthan500mL/day,andaurinesodiumleveloflessthan10mEq/Larepresent.[2]Urineosmolalityisgreaterthanplasmaosmolality.

Portalhypertension

Duringangiography,acathetermaybeplacedselectivelyviaeitherthetransjugularortransfemoralrouteintothehepaticveintomeasureportalpressure.

Hepaticencephalopathy

Anelevatedarterialorfreevenousserumammonialevelistheclassiclaboratoryabnormalityreportedinpatientswithhepaticencephalopathy.

Electroencephalographymaybehelpfulintheinitialworkupofapatientwithcirrhosisandalteredmentalstatus,whenrulingoutseizureactivitymaybenecessary.

Computedtomography(CT)scanningandMRIstudiesofthebrainmaybeimportantinrulingoutintracraniallesionswhenthediagnosisofhepaticencephalopathyisinquestion.

Ascites

Paracentesisisessentialindeterminingwhetherascitesiscausedbyportalhypertensionorbyanotherprocess.

Management

Specificmedicaltherapiesmaybeappliedtomanyliverdiseasesinanefforttodiminishsymptomsandtopreventorforestallthedevelopmentofcirrhosis.Examplesofsuchtreatmentsincludethefollowing:

PrednisoneandazathioprineForautoimmunehepatitisInterferonandotherantiviralagentsForhepatitisBandCPhlebotomyForhemochromatosisUrsodeoxycholicacidForprimarybiliarycirrhosisTrientineandzincForWilsondisease

Oncecirrhosisdevelops,treatmentisaimedatthemanagementofcomplicationsastheyarise.Examplesincludethefollowing:

HepatorenalsyndromeKidneyfunctionusuallyrecoverswhenpatientswithcirrhosisandhepatorenalsyndromeundergolivertransplantationpatientswithearlyhepatorenalsyndromemaybesalvagedbyaggressiveexpansionofintravascularvolumewithalbuminandfreshfrozenplasmaandbyavoidanceofdiureticsHepaticencephalopathyPharmacologictreatmentincludestheadministrationoflactuloseandantibioticsAscitesTreatmentcanincludesodiumrestrictionandtheuseofdiuretics,largevolumeparacentesis,andshunts(peritoneovenous,portosystemic,transjugularintrahepaticportosystemic)

Livertransplantation

Patientsshouldbereferredforconsiderationforlivertransplantationafterthefirstsignsofhepaticdecompensation.

Overview

Cirrhosisrepresentsthefinalcommonhistologicpathwayforawidevarietyofchronicliverdiseases.ThetermcirrhosiswasfirstintroducedbyLaennecin1826.ItisderivedfromtheGreektermscirrhusandreferstotheorangeortawnysurfaceoftheliverseenatautopsy.

Cirrhosisisdefinedhistologicallyasadiffusehepaticprocesscharacterizedbyfibrosisandtheconversionofnormalliverarchitectureintostructurallyabnormalnodules.Theprogressionofliverinjurytocirrhosismayoccuroverweekstoyears.Indeed,patientswithhepatitisCmayhavechronichepatitisforaslongas40yearsbeforeprogressingtocirrhosis.

Manyformsofliverinjuryaremarkedbyfibrosis,whichisdefinedasanexcessdepositionofthecomponentsoftheextracellularmatrix(ie,collagens,glycoproteins,proteoglycans)withintheliver.Thisresponsetoliverinjurypotentiallyisreversible.Bycontrast,inmostpatients,cirrhosisisnotareversibleprocess.

Inadditiontofibrosis,thecomplicationsofcirrhosisinclude,butarenotlimitedto,portalhypertension,ascites,hepatorenalsyndrome,andhepaticencephalopathy.

Oftenapoorcorrelationexistsbetweenthehistologicfindingsincirrhosisandtheclinicalpicture.Somepatientswithcirrhosisarecompletelyasymptomaticandhaveareasonablynormallifeexpectancy.Otherindividualshaveamultitudeofthemostseveresymptomsofendstageliverdiseaseandhavealimitedchanceforsurvival.Commonsignsandsymptomsmaystemfromdecreasedhepaticsyntheticfunction(eg,coagulopathy),decreaseddetoxificationcapabilitiesoftheliver(eg,hepaticencephalopathy),orportalhypertension(eg,varicealbleeding).

Patienteducation

Forpatienteducationinformation,seetheMentalHealthCenter,aswellasAlcoholism.

InAugust2012,theCentersforDiseaseControlandPrevention(CDC)expandedtheirexisting,riskbasedtestingguidelinestorecommenda1timebloodtestforhepatitisCvirus(HCV)infectioninbabyboomersthegenerationbornbetween1945and1965,whoaccountforapproximatelythreefourthsofallchronicHCVinfectionsintheUnitedStateswithoutpriorascertainmentofHCVrisk(seeRecommendationsfortheIdentificationofChronicHepatitisCVirusInfectionAmong



PersonsBornDuring19451965).[3]OnetimeHCVtestinginthispopulationcouldidentifynearly808,600additionalpeoplewithchronicinfection.AllindividualsidentifiedwithHCVshouldbescreenedand/ormanagedforalcoholabuse,followedbyreferraltopreventativeand/ortreatmentservices,asappropriate.

Epidemiology

Chronicliverdiseaseandcirrhosisresultinabout35,000deathseachyearintheUnitedStates.CirrhosisistheninthleadingcauseofdeathintheUnitedStatesandisresponsiblefor1.2%ofallUSdeaths.Manypatientsdiefromthediseaseintheirfifthorsixthdecadeoflife.

Eachyear,2000additionaldeathsareattributedtofulminanthepaticfailure(FHF).FHFmaybecausedviralhepatitis(eg,hepatitisAandB),drugs(eg,acetaminophen),toxins(eg,Amanitaphalloides,theyellowdeathcapmushroom),autoimmunehepatitis,Wilsondisease,oravarietyoflesscommonetiologies.Cryptogeniccausesareresponsibleforonethirdoffulminantcases.PatientswiththesyndromeofFHFhavea5080%mortalityrateunlesstheyaresalvagedbylivertransplantation.

Etiology

AlcoholicliverdiseaseoncewasconsideredtobethepredominantsourceofcirrhosisintheUnitedStates,buthepatitisChasemergedasthenation'sleadingcauseofchronichepatitisandcirrhosis.

Manycasesofcryptogeniccirrhosisappeartohaveresultedfromnonalcoholicfattyliverdisease(NAFLD).Whencasesofcryptogeniccirrhosisarereviewed,manypatientshave1ormoreoftheclassicriskfactorsforNAFLD:obesity,diabetes,andhypertriglyceridemia.[4]Itispostulatedthatsteatosismayregressinsomepatientsashepaticfibrosisprogresses,makingthehistologicdiagnosisofNAFLDdifficult.

UptoonethirdofAmericanshaveNAFLD.About23%ofAmericanshavenonalcoholicsteatohepatitis(NASH),inwhichfatdepositioninthehepatocyteiscomplicatedbyliverinflammationandfibrosis.Itisestimatedthat10%ofpatientswithNASHwillultimatelydevelopcirrhosis.NAFLDandNASHareanticipatedtohaveamajorimpactontheUnitedStates'publichealthinfrastructure.

MostcommoncausesofcirrhosisintheUnitedStates

Seethelistbelow:

HepatitisC(26%)Alcoholicliverdisease(21%)HepatitisCplusalcoholicliverdisease(15%)Cryptogeniccauses(18%)ManycasesactuallyareduetoNAFLDHepatitisBMaybecoincidentwithhepatitisD(15%)Miscellaneous(5%)

Miscellaneouscausesofchronicliverdiseaseandcirrhosis

Seethelistbelow:

AutoimmunehepatitisPrimarybiliarycirrhosisSecondarybiliarycirrhosisAssociatedwithchronicextrahepaticbileductobstructionPrimarysclerosingcholangitisHemochromatosisWilsondiseaseAlpha1antitrypsindeficiencyGranulomatousdiseaseEg,sarcoidosisTypeIVglycogenstoragediseaseDruginducedliverdiseaseEg,methotrexate,alphamethyldopa,amiodaroneVenousoutflowobstructionEg,BuddChiarisyndrome,venoocclusivediseaseChronicrightsidedheartfailureTricuspidregurgitation

HepaticFibrosis

Thedevelopmentofhepaticfibrosisreflectsanalterationinthenormallybalancedprocessesofextracellularmatrixproductionanddegradation.[5]Theextracellularmatrix,thenormalscaffoldingforhepatocytes,iscomposedofcollagens(especiallytypesI,III,andV),glycoproteins,andproteoglycans.

Stellatecells,locatedintheperisinusoidalspace,areessentialfortheproductionofextracellularmatrix.Stellatecells,whichwereonceknownasItocells,lipocytes,orperisinusoidalcells,maybecomeactivatedintocollagenformingcellsbyavarietyofparacrinefactors.Suchfactorsmaybereleasedbyhepatocytes,Kupffercells,andsinusoidalendotheliumfollowingliverinjury.Asanexample,increasedlevelsofthecytokinetransforminggrowthfactorbeta1(TGFbeta1)areobservedinpatientswithchronichepatitisCandthosewithcirrhosis.TGFbeta1,inturn,stimulatesactivatedstellatecellstoproducetypeIcollagen.

IncreasedcollagendepositioninthespaceofDisse(thespacebetweenhepatocytesandsinusoids)andthediminutionofthesizeofendothelialfenestraeleadtothecapillarizationofsinusoids.Activatedstellatecellsalsohavecontractileproperties.Capillarizationandconstrictionofsinusoidsbystellatecellscontributetothedevelopmentofportalhypertension.

Futuredrugstrategiestopreventfibrosismayfocusonreducinghepaticinflammation,inhibitingstellatecellactivation,inhibitingthefibrogenicactivitiesof



stellatecells,andstimulatingmatrixdegradation.

PortalHypertension

Causes

Thenormalliverhastheabilitytoaccommodatelargechangesinportalbloodflowwithoutappreciablealterationsinportalpressure.Portalhypertensionresultsfromacombinationofincreasedportalvenousinflowandincreasedresistancetoportalbloodflow.

Patientswithcirrhosisdemonstrateincreasedsplanchnicarterialflowand,accordingly,increasedsplanchnicvenousinflowintotheliver.Increasedsplanchnicarterialflowisexplainedpartlybydecreasedperipheralvascularresistanceandincreasedcardiacoutputinthepatientwithcirrhosis.Nitricoxideappearstobethemajordrivingforceforthisphenomenon.[6]

Furthermore,evidenceforsplanchnicvasodilationexists.Putativesplanchnicvasodilatorsincludeglucagon,vasoactiveintestinalpeptide,substanceP,prostacyclin,bileacids,tumornecrosisfactoralpha(TNFalpha),andnitricoxide.

Increasedresistanceacrossthesinusoidalvascularbedoftheliveriscausedbyfixedfactorsanddynamicfactors.Twothirdsofintrahepaticvascularresistancecanbeexplainedbyfixedchangesinthehepaticarchitecture.Suchchangesincludetheformationofregeneratingnodulesand,aftertheproductionofcollagenbyactivatedstellatecells,depositionofthecollagenwithinthespaceofDisse.

Dynamicfactorsaccountforonethirdofintrahepaticvascularresistance.Stellatecellsserveascontractilecellsforadjacenthepaticendothelialcells.Thenitricoxideproducedbytheendothelialcells,inturn,controlstherelativedegreeofvasodilationorvasoconstrictionproducedbythestellatecells.Incirrhosis,decreasedlocalproductionofnitricoxidebyendothelialcellspermitsstellatecellcontraction,withresultingvasoconstrictionofthehepaticsinusoid.(Thiscontrastswiththeperipheralcirculation,wheretherearehighcirculatinglevelsofnitricoxideincirrhosis.)Increasedlocallevelsofvasoconstrictingchemicals,suchasendothelin,mayalsocontributetosinusoidalvasoconstriction.

Theportalhypertensionofcirrhosisiscausedbythedisruptionofhepaticsinusoids.However,portalhypertensionmaybeobservedinavarietyofnoncirrhoticconditions.

Prehepaticcauses

Prehepaticcausesincludesplenicveinthrombosisandportalveinthrombosis.Theseconditionscommonlyareassociatedwithhypercoagulablestatesandwithmalignancy(eg,pancreaticcancer).

Intrahepaticcauses

Intrahepaticcausesofportalhypertensionaredividedintopresinusoidal,sinusoidal,andpostsinusoidalconditions.Theclassicsinusoidalcauseofportalhypertensioniscirrhosis.

TheclassicformofpresinusoidalportalhypertensioniscausedbythedepositionofSchistosomaoocytesinpresinusoidalportalvenules,withthesubsequentdevelopmentofgranulomataandportalfibrosis.Schistosomiasisisthemostcommonnoncirrhoticcauseofvaricealbleedingworldwide.SchistosomamansoniinfectionisdescribedinPuertoRico,CentralandSouthAmerica,theMiddleEast,andAfrica.SjaponicumisdescribedintheFarEast.Shematobium,observedintheMiddleEastandAfrica,canproduceportalfibrosisbutmorecommonlyisassociatedwithurinarytractdepositionofeggs.

Theclassicpostsinusoidalconditionisanentityknownasvenoocclusivedisease.ObliterationoftheterminalhepaticvenulesmayresultfromingestionofpyrrolizidinealkaloidsinComfreyteaorJamaicanbushteaorfollowingthehighdosechemotherapythatprecedesbonemarrowtransplantation.

Posthepaticcauses

Posthepaticcausesofportalhypertensionmayincludechronicrightsidedheartfailureandtricuspidregurgitationandobstructinglesionsofthehepaticveinsandinferiorvenacava.Thelatterconditions,andthesymptomstheyproduce,aretermedBuddChiarisyndrome.Predisposingconditionsincludehypercoagulablestates,tumorinvasionintothehepaticveinorinferiorvenacava,andmembranousobstructionoftheinferiorvenacava.InferiorvenacavawebsareobservedmostcommonlyinSouthandEastAsiaandarepostulatedtobeduetonutritionalfactors.

SymptomsofBuddChiarisyndromeareattributedtodecreasedoutflowofbloodfromtheliver,withresultinghepaticcongestionandportalhypertension.Thesesymptomsincludehepatomegaly,abdominalpain,andascites.Cirrhosisensuesonlylaterinthecourseofdisease.DifferentiatingBuddChiarisyndromefromcirrhosisbyhistoryorphysicalexaminationmaybedifficult.Thus,BuddChiarisyndromemustbeincludedinthedifferentialdiagnosisofconditionsthatproduceascitesandvarices.

Hepaticveinpatencyischeckedmostreadilybyperformingabdominalultrasonography,withDopplerexaminationofthehepaticvessels.Abdominalcomputedtomography(CT)scanningwithintravenous(IV)contrast,abdominalmagneticresonanceimaging(MRI),andvisceralangiographyalsomayprovideinformationregardingthepatencyofhepaticvessels.

Measurement

Widespreaduseofthetransjugularintrahepaticportosystemicshunt(TIPS)procedureinthe1990sforthemanagementofvaricealbleedingledtoaresurgenceofclinicians'interestinmeasuringportalpressure.Duringangiography,acathetermaybeplacedselectivelyviaeitherthetransjugularortransfemoralrouteintothe



hepaticvein.Inthehealthypatient,freehepaticveinpressure(FHVP)isequaltoinferiorvenacavapressure.FHVPisusedasaninternalzeroreferencepoint.

Wedgedhepaticvenouspressure(WHVP)ismeasuredbyinflatingaballoonatthecathetertip,thusoccludingahepaticveinbranch.MeasurementoftheWHVPprovidesacloseapproximationofportalpressure.TheWHVPactuallyisslightlylowerthantheportalpressurebecauseofsomedissipationofpressureinthesinusoidalbed.TheWHVPandportalpressureareelevatedinpatientswithsinusoidalportalhypertension,asisobservedincirrhosis.

Complications

Thehepaticvenouspressuregradient(HVPG)isdefinedasthedifferenceinpressurebetweentheportalveinandtheinferiorvenacava.Thus,theHVPGisequaltotheWHVPvalueminustheFHVPvalue(ie,HVPG=WHVPFHVP).ThenormalHVPGis36mmHg.

Portalhypertensionisdefinedasasustainedelevationofportalpressureabovenormal.AnHVPGof8mmHgisbelievedtobethethresholdabovewhichascitespotentiallycandevelop.AnHVPGof12mmHgisthethresholdforthepotentialformationofvarices.Highportalpressuresmaypredisposepatientstoanincreasedriskofvaricealhemorrhage.[7]

AscitesAscites,whichisanaccumulationofexcessivefluidwithintheperitonealcavity,canbeacomplicationofeitherhepaticornonhepaticdisease.The4mostcommoncausesofascitesinNorthAmericaandEuropearecirrhosis,neoplasm,congestiveheartfailure,andtuberculousperitonitis.

Inthepast,asciteswasclassifiedasbeingatransudateoranexudate.Intransudativeascites,fluidwassaidtocrossthelivercapsulebecauseofanimbalanceinStarlingforces.Ingeneral,ascitesproteinwouldbelessthan2.5g/dLinthisformofascites.Aclassiccauseoftransudativeasciteswouldbeportalhypertensionsecondarytocirrhosisandcongestiveheartfailure.

Inexudativeascites,fluidwassaidtoweepfromaninflamedortumorladenperitoneum.Ingeneral,ascitesproteininexudativeasciteswouldbegreaterthan2.5g/dL.Causesoftheconditionwouldincludeperitonealcarcinomatosisandtuberculousperitonitis.

Nonperitonealcauses

Attributingascitestodiseasesofnonperitonealorperitonealoriginismoreuseful.ThankstotheworkofBruceRunyon,theserumascitesalbumingradient(SAAG)hascomeintocommonclinicalusefordifferentiatingtheseconditions.NonperitonealdiseasesproduceasciteswithaSAAGgreaterthan1.1g/dL.(SeeTable1,below.)[8]

Table1.NonperitonealCausesofAscites[9](OpenTableinanewwindow)

CausesofNonperitonealAscites Examples

Intrahepaticportalhypertension

Cirrhosis

Fulminanthepaticfailure

Venoocclusivedisease

Extrahepaticportalhypertension

Hepaticveinobstruction(ie,BuddChiarisyndrome)

Congestiveheartfailure

Hypoalbuminemia

Nephroticsyndrome

ProteinlosingenteropathyMalnutrition

Miscellaneousdisorders

Myxedema

Ovariantumors

Pancreaticascites



Biliaryascites

Chylous

Secondarytomalignancy

Secondarytotrauma

Secondarytoportalhypertension

Chylousascites,causedbyobstructionofthethoracicductorcisternachyli,mostoftenisduetomalignancy(eg,lymphoma)butoccasionallyisobservedpostoperativelyandfollowingradiationinjury.Chylousascitesalsomaybeobservedinthesettingofcirrhosis.Thetriglycerideconcentrationoftheascitesisgreaterthan110mg/dLandgreaterthanthatobservedinplasma.Patientsshouldbeplacedonalowfatdietthatissupplementedwithmediumchaintriglycerides.Treatmentwithdiureticsandlargevolumeparacentesismayberequired.

Peritonealcauses

PeritonealdiseasesproduceasciteswithaSAAGoflessthan1.1g/dL.(SeeTable2,below.)

Table2.PeritonealCausesofAscites[9](OpenTableinanewwindow)

CausesofPeritonealAscites Examples

Malignantascites

Primaryperitonealmesothelioma

Secondaryperitonealcarcinomatosis

Granulomatousperitonitis

Tuberculousperitonitis

Fungalandparasiticinfections(eg,Candida,

Histoplasma,Cryptococcus,Schistosomamansoni,Strongyloides,Entamoebahistolytica)

Sarcoidosis

Foreignbodies(ie,talc,cottonandwoodfibers,

starch,barium)

Vasculitis

Systemiclupuserythematosus

HenochSchnleinpurpura

Miscellaneousdisorders

Eosinophilicgastroenteritis

Whippledisease

Endometriosis

Theroleofportalhypertensioninthepathogenesisofcirrhoticascites



TheformationofascitesincirrhosisdependsonthepresenceofunfavorableStarlingforceswithinthehepaticsinusoidandonsomedegreeofrenaldysfunction.Patientswithcirrhosisareobservedtohaveincreasedhepaticlymphaticflow.

FluidandplasmaproteinsdiffusefreelyacrossthehighlypermeablesinusoidalendotheliumintothespaceofDisse.FluidinthespaceofDisse,inturn,entersthelymphaticchannelsthatrunwithintheportalandcentralvenousareasoftheliver.

Becausethetranssinusoidaloncoticgradientisapproximatelyzero,theincreasedsinusoidalpressurethatdevelopsinportalhypertensionincreasestheamountoffluidenteringthespaceofDisse.Whentheincreasedhepaticlymphproductionobservedinportalhypertensionexceedstheabilityofthecisternachyliandthoracicducttoclearthelymph,fluidcrossesintotheliverinterstitium.Fluidmaythenextravasateacrossthelivercapsuleintotheperitonealcavity.

Theroleofrenaldysfunctioninthepathogenesisofcirrhotic

ascites

Patientswithcirrhosisexperiencesodiumretention,impairedfreewaterexcretion,andintravascularvolumeoverload.Theseabnormalitiesmayoccureveninthesettingofanormalglomerularfiltrationrate.Theyare,tosomeextent,duetoincreasedlevelsofreninandaldosterone.

Theperipheralarterialvasodilationhypothesisstatesthatsplanchnicarterialvasodilation,drivenbyhighnitricoxidelevels,leadstointravascularunderfilling.Thiscausesstimulationofthereninangiotensinsystemandthesympatheticnervoussystemandalsoresultsinantidiuretichormonerelease.Theseeventsarefollowedbyanincreaseinsodiumandwaterretentionandinplasmavolume,aswellasbytheoverflowofascitesintotheperitonealcavity.

Clinicalfeaturesofascites

Ascitesissuggestedbythepresenceofthefollowingfindingsuponphysicalexamination:

AbdominaldistentionBulgingflanksShiftingdullnessElicitationofa"puddlesign"inpatientsinthekneeelbowposition

Afluidwavemaybeelicitedinpatientswithmassivetenseascites.However,physicalexaminationfindingsaremuchlesssensitivethanabdominalultrasonography,whichcandetectaslittleas30mLoffluid.Furthermore,ultrasonographywithDopplercanhelptoassessthepatencyofhepaticvessels.

Factorsassociatedwithworseningofascitesincludeexcessfluidorsaltintake,malignancy,venousocclusion(eg,BuddChiarisyndrome),progressiveliverdisease,andspontaneousbacterialperitonitis(SBP).

Spontaneousbacterialperitonitis

SBPisobservedin1526%ofpatientshospitalizedwithascites.Thesyndromearisesmostcommonlyinpatientswhoselowproteinascites(



withcirrhosis,herniorrhaphycarriesmultiplepotentialrisks,suchasintraoperativebleeding,postoperativeinfection,andliverfailure,becauseofanesthesiainducedreductionsinhepaticbloodflow.However,theserisksbecomeacceptableinpatientswithseveresymptomsfromtheirhernia.Urgentsurgeryisnecessaryinthepatientwhoseherniahasbeencomplicatedbybowelincarceration.

Othercomplicationsofmassiveascites

Patientswithmassiveascitesmayexperienceabdominaldiscomfort,depressedappetite,anddecreasedoralintake.Diaphragmaticelevationmayleadtosymptomsofdyspnea.Pleuraleffusionsmayresultfromthepassageofasciticfluidacrosschannelsinthediaphragm.

Paracentesisinthediagnosisofascites

Paracentesisisessentialindeterminingwhetherascitesiscausedbyportalhypertensionorbyanotherprocess.Ascitesstudiesalsoareusedtoruleoutinfectionandmalignancy.Paracentesisshouldbeperformedinallpatientswitheithernewonsetofascitesorworseningascites.ParacentesisalsoshouldbeperformedwhenSBPissuggestedbythepresenceofabdominalpain,fever,leukocytosis,orworseninghepaticencephalopathy.Somearguethatparacentesisshouldbeperformedinallpatientswithcirrhosiswhohaveascitesatthetimeofhospitalization,giventhesignificantpossibilityofasymptomaticSBP.(SeeTable3,below.)

Table3.AscitesTests(OpenTableinanewwindow)

Routine Optional Special

Cellcount

Glucose(minimaluse) Cytology

Albumin Lactatedehydrogenase Tuberculosissmearandculture

Culture Gramstain Triglycerides(toruleoutchylousascites)

Totalprotein

Bilirubin(toruleoutbiliaryleakwhenclinicallysuspected)

Amylase(toruleoutpancreaticductleakwhenclinicallysuspected)

Asciticfluidwithmorethan250PMNs/mm3definesneutrocyticascitesandSBP.Manycasesofascitesfluidwithmorethan1000PMNs/mm3(andcertainly>5000PMNs/mm3)areassociatedwithappendicitisoraperforatedviscuswithresultingbacterialperitonitis.Appropriateradiologicstudiesmustbeperformedinsuchpatientstoruleoutsurgicalcausesofperitonitis.

Lymphocytepredominantascitesraisesconcernsaboutthepossibilityofunderlyingmalignancyortuberculosis.Similarly,grosslybloodyascitesmaybeobservedinmalignancyandtuberculosis.(Bloodyascitesisseeninfrequentlyinuncomplicatedcirrhosis.)AcommonclinicaldilemmaishowtointerprettheascitesPMNcountinthesettingofbloodyascites.Thisauthorrecommendssubtractionof1PMNforevery250redbloodcells(RBCs)inascitestoascertainacorrectedPMNcount.

Theyieldofascitesculturestudiesmaybeincreasedbydirectlyinoculating10mLofascitesintoaerobicandanaerobicculturebottlesatthepatient'sbedside.[16]

Medicaltreatmentofascites

Therapyforascitesshouldbetailoredtothepatient'sneeds.Somepatientswithmildascitesrespondtosodiumrestrictionordiureticstakenonceortwiceperweek.Otherpatientsrequireaggressivediuretictherapy,carefulmonitoringofelectrolytes,andoccasionalhospitalizationtofacilitateevenmoreintensivediuresis.

Thedevelopmentofmassiveascitesthatisrefractorytomedicaltherapyhasdireprognosticimplications,withonly50%ofpatientssurviving6months.[17]

Sodiumrestriction

Saltrestrictionisthefirstlineoftherapy.Ingeneral,patientsbeginwithadietcontaininglessthan2000mgofsodiumdaily.Somepatientswithrefractoryascitesrequireadietcontaininglessthan500mgofsodiumdaily.However,ensuringthatpatientsdonotconstructdietsthatmightplacethematriskforcalorieandproteinmalnutritionisimportant.Indeed,thebenefitofcommerciallyavailableliquidnutritionalsupplements(whichoftencontainmoderateamountsofsodium)oftenexceedstheriskofslightlyincreasingthepatient'ssaltintake.

Diuretics

Diureticsshouldbeconsideredthesecondlineoftherapy.Spironolactone(Aldactone)blocksthealdosteronereceptoratthedistaltubule.Itisdosedat50300mgoncedaily.Althoughthedrughasarelativelyshorthalflife,itsblockadeofthealdosteronereceptorlastsforatleast24hours.Adverseeffectsofspironolactoneincludehyperkalemia,gynecomastia,andlactation.Otherpotassiumsparingdiuretics,includingamilorideandtriamterene,maybeusedasalternativeagents,especiallyinpatientscomplainingofgynecomastia.

Furosemide(Lasix)maybeusedasasoloagentorincombinationwithspironolactone.ThedrugblockssodiumreuptakeintheloopofHenle.Itisdosedat40240mgdailyin12divideddoses.Patientsinfrequentlyneedpotassiumrepletionwhenfurosemideisdosedincombinationwithspironolactone.AnItalianstudybyAngelietalfoundsequentialdosingwithapotassiumsparingdiureticplusfurosemidetobesuperiorforpatientswithmoderateasciteswithoutrenalfailure



whencomparedwithpotassiumsparingdiureticmonotherapy.[18]

Aggressivediuretictherapyinhospitalizedpatientswithmassiveascitescansafelyinduceaweightlossof0.51kgdaily,providedthatpatientsundergocarefulmonitoringofrenalfunction.Diuretictherapyshouldbeheldintheeventofelectrolytedisturbances,azotemia,orinductionofhepaticencephalopathy.

Albumin

Thusfar,evidencebasedmedicinehasnotfirmlysupportedtheuseofalbuminasanaidtodiuresisinapatientwithcirrhosiswhoishospitalized.Theauthor'sanecdotalexperiencesuggeststhatalbuminmayincreasetheefficacyandsafetyofdiuretics.Theauthor'spracticeinhospitalizedpatientswhoarehypoalbuminemicistoadministerIVfurosemidefollowingIVinfusionofalbuminat25gtwicedaily,inadditiontoprovidingongoingtherapywithspironolactone.Onearticlesupportedtheuseofchronicalbumininfusionstoachievediuresisinpatientswithdiureticresistantascites.[19]

AlbumininfusionmayprotectagainstthedevelopmentofrenalinsufficiencyinpatientswithSBP.Patientsreceivingcefotaximeandalbuminat1g/kgdailyexperiencedalowerriskofrenalfailureandalowerinhospitalmortalityratethanpatientstreatedwithcefotaximeandconventionalfluidmanagement.[20]

V2receptorantagonists

VasopressinV2receptorantagonistsareaclassofagentswiththepotentialtoincreasefreewaterexcretion,improvediuresis,anddecreasetheneedforparacentesis.However,nosuchagenthasreceivedUSFoodandDrugAdministration(FDA)approvalforthisindication.

Tolvaptan(Samsca,OtsukaPharmaceuticalCoTokyo,Japan)isanoralV2receptorantagonistitreceivedFDAapprovalin2009onlyforthemanagementofhyponatremia.Ablackboxwarningcautionsagainsttreatmentinitiationinoutpatients.Furthermore,itmaybeassociatedwithanincreasedincidenceofGIbleedinginpatientswithcirrhosis.Theauthoradvisesagainstitsuseforascitesmanagementatthistime.

Largevolumeparacentesis

Aggressivediuretictherapyisineffectiveincontrollingascitesinapproximately510%ofpatients.Suchpatientswithmassiveascitesmayneedtoundergolargevolumeparacentesistoobtainrelieffromsymptomsofabdominaldiscomfort,anorexia,ordyspnea.Theprocedurealsomayhelptoreducetheriskofumbilicalherniarupture.

Largevolumeparacentesiswasfirstusedinancienttimes.Itfelloutoffavorfromthe1950sthroughthe1980swiththeadventofdiuretictherapyandfollowingahandfulofcasereportsdescribingparacentesisinducedazotemia.In1987,Ginesandcolleaguesdemonstratedthatlargevolumeparacentesiscouldbeperformedwithminimalornoimpactonrenalfunction.[21]Thisandotherstudiesshowedthat515Lofascitescouldberemovedsafelyatonetime.

Largevolumeparacentesisisthoughttobesafeinpatientswithperipheraledemaandinpatientsnotcurrentlytreatedwithdiuretics.Debateexistswhethercolloidinfusions(eg,with510gofalbuminper1Lofascitesremoved)arenecessarytopreventintravascularvolumedepletioninpatientswhoarereceivingongoingdiuretictherapyorinpatientswithmildormoderate,underlyingrenalinsufficiency.

Peritoneovenousshunts

LeVeenshuntsandDenvershuntsaredevicesthatpermitthereturnofascitesfluidandproteinstotheintravascularspace.Plastictubinginsertedsubcutaneouslyunderlocalanesthesiaconnectstheperitonealcavitytotheinternaljugularveinorsubclavianveinviaapumpingchamber.Thesedevicesaresuccessfulatrelievingascitesandreversingproteinlossinsomepatients.However,shuntsmayclotandrequirereplacementin30%ofpatients.

Seriouscomplicationsareobservedinatleast10%oftherecipientsofthesedevices,includingperitonealinfection,sepsis,disseminatedintravascularcoagulation,congestiveheartfailure,anddeath.TheauthorconsidersperitoneovenousshuntstobealastresortforpatientswithrefractoryasciteswhoarenotcandidatesforTIPSorlivertransplantation.Thesafetyofrepeatlargevolumeparacentesisproceduresmayactuallyoutweighthesafetyofperitoneovenousshuntplacement.

Portosystemicshuntsandtransjugularintrahepaticportosystemicshunts

Theprimeindicationforportocavalshuntsurgeryisthemanagementofrefractoryvaricealbleeding.Since1945,however,themedicalfieldhasrecognizedthatportocavalshunts,bydecompressingthehepaticsinusoid,mayimproveascites.Theperformanceofasidetosideportocavalshuntforascitesmanagementmustbeweighedagainsttheapproximate5%mortalityrateassociatedwiththissurgeryandthechance(ashighas30%)ofinducinghepaticencephalopathy.

ATIPSisaneffectivetoolinmanagingmassiveascitesinsomepatients.Ideally,TIPSplacementproducesadecreaseinsinusoidalpressureandinplasmareninandaldosteronelevels,withsubsequentimprovedurinarysodiumexcretion.Inonestudy,74%ofpatientswithrefractoryascitesachievedcompleteremissionofasciteswithin3monthsofTIPSplacement.[22]Typically,aboutonehalfofappropriatelyselectedpatientsundergoingTIPSachievesignificantreliefofascites.

MultiplestudieshavedemonstratedthataTIPSissuperiortolargevolumeparacentesiswhenitcomestothecontrolofascites.[23]OnemetaanalysisofindividualpatientdatademonstratedanimprovementintransplantfreelifeexpectancyinpatientswhosemassiveasciteswastreatedwithaTIPS,asopposed



tolargevolumeparacentesis.[24]However,thecreationofaTIPShasthepotentialtoworsenpreexistinghepaticencephalopathyandexacerbateliverdysfunctionin

patientswithsevere,underlyingliverfailure.[25]

BothapreTIPSbilirubinlevelofgreaterthan3mg/dLandapreTIPSModelfor

EndStageLiverDisease(MELD)scoreofgreaterthan18(seetheMELDScore

calculator)areassociatedwithanincreasedmortalityratewhenaTIPSiscreated

forthemanagementofascites.[26,27]Intheauthor'sopinion,TIPSuseshouldbereservedforpatientswithChildClassBcirrhosisorpatientswithChildClassC

cirrhosiswithoutseverecoagulopathyorencephalopathy.

Inthe1990s,shuntstenosiswasobservedinonehalfofcaseswithin1yearofTIPS

placement,necessitatingangiographicrevision.Althoughtheadventofcoated

stentsappearstohavereducedtheincidenceofshuntstenosis,patientsmuststill

bewillingtoreturntothehospitalforDopplerandangiographicfollowupofTIPS

patency.

Livertransplantation

Patientswithmassiveasciteshave1yearsurvivalrateoflessthan50%.Liver

transplantationshouldbeconsideredasapotentialmeansofsalvagingthepatient

priortotheonsetofintractableliverfailureorhepatorenalsyndrome.

HepatorenalSyndrome

Thissyndromerepresentsacontinuumofrenaldysfunctionthatmaybeobservedin

patientswithacombinationofcirrhosisandascites.Hepatorenalsyndromeis

causedbythevasoconstrictionoflargeandsmallrenalarteriesandtheimpaired

renalperfusionthatresults.[28]

Thesyndromemayrepresentanimbalancebetweenrenalvasoconstrictorsand

vasodilators.Plasmalevelsofanumberofvasoconstrictingsubstancesincluding

angiotensin,antidiuretichormone,andnorepinephrineareelevatedinpatientswith

cirrhosis.Renalperfusionappearstobeprotectedbyvasodilators,including

prostaglandinsE2andI2andatrialnatriureticfactor.

Nonsteroidalantiinflammatorydrugs(NSAIDs)inhibitprostaglandinsynthesis.They

maypotentiaterenalvasoconstriction,witharesultingdropinglomerularfiltration.

Thus,theuseofNSAIDsiscontraindicatedinpatientswithdecompensated

cirrhosis.

Mostpatientswithhepatorenalsyndromearenotedtohaveminimalhistologic

changesinthekidneys.Kidneyfunctionusuallyrecoverswhenpatientswith

cirrhosisandhepatorenalsyndromeundergolivertransplantation.Infact,akidney

donatedbyapatientdyingfromhepatorenalsyndromefunctionsnormallywhen

transplantedintoarenaltransplantrecipient.

Typesofhepatorenalsyndrome

Hepatorenalsyndromeprogressionmaybeslow(typeII)orrapid(typeI).[29]TypeIdiseasefrequentlyisaccompaniedbyrapidlyprogressiveliverfailure.Hemodialysis

offerstemporarysupportforsuchpatients.Theseindividualsaresalvagedonlyby

performanceoflivertransplantation.Exceptionstothisrulearethepatientswith

fulminanthepaticfailure(FHF)orseverealcoholichepatitiswhospontaneously

recoverliverandkidneyfunction.IntypeIIhepatorenalsyndrome,patientsmay

havestableorslowlyprogressiverenalinsufficiency.Manysuchpatientsdevelop

ascitesthatisresistanttomanagementwithdiuretics.

Diagnosis

Hepatorenalsyndromeisdiagnosedwhenacreatinineclearancerateoflessthan

40mL/minispresentorwhenaserumcreatininelevelofgreaterthan1.5mg/dL,a

urinevolumeoflessthan500mL/day,andaurinesodiumleveloflessthan10mEq/L

arepresent.[2]Urineosmolalityisgreaterthanplasmaosmolality.

Inhepatorenalsyndrome,renaldysfunctioncannotbeexplainedbypreexisting

kidneydisease,prerenalazotemia,theuseofdiuretics,orexposuretonephrotoxins.

Clinically,thediagnosismaybereachedifcentralvenouspressureisdeterminedto

benormalorifnoimprovementinrenalfunctionoccursfollowingtheinfusionofat

least1.5Lofaplasmaexpander.

Treatment

Nephrotoxicmedications,includingaminoglycosideantibiotics,shouldbeavoidedin

patientswithcirrhosis.Patientswithearlyhepatorenalsyndromemaybesalvaged

byaggressiveexpansionofintravascularvolumewithalbuminandfreshfrozen

plasmaandbyavoidanceofdiuretics.Theuseofrenaldosedopamineisnot

effective.

Anumberofinvestigatorshaveemployedsystemicvasoconstrictorsinanattemptto

reversetheeffectsofnitricoxideonperipheralarterialvasodilation.InEurope,

administrationofIVterlipressin(ananalogofvasopressinnotavailableintheUnited

States)improvedrenaldysfunctioninpatientswithhepatorenalsyndrome.[30,31]

Acombinationofmidodrine(anoralalphaagonist),subcutaneousoctreotide,and

albumininfusionhasalsobeendemonstratedtoimproverenalfunctioninsmall

cohortsofpatientswithhepatorenalsyndrome.[32]

HepaticEncephalopathy

Hepaticencephalopathy,asyndromeobservedinsomepatientswithcirrhosis,is

markedbypersonalitychanges,intellectualimpairment,andadepressedlevelof

consciousness.Thediversionofportalbloodintothesystemiccirculationappearsto



beaprerequisiteforthesyndrome.Indeed,hepaticencephalopathymaydevelopinpatientswithoutcirrhosiswhoundergoportocavalshuntsurgery.

Pathogenesis

Anumberoftheorieshavebeenpostulatedtoexplainthepathogenesisofhepaticencephalopathyinpatientswithcirrhosis.Patientsmayhavealteredbrainenergymetabolismandincreasedpermeabilityofthebloodbrainbarrier.Thelattermayfacilitatethepassageofneurotoxinsintothebrain.Putativeneurotoxinsincludeshortchainfattyacids,mercaptans,falseneurotransmitters(eg,tyramine,octopamine,betaphenylethanolamines),ammonia,andgammaaminobutyricacid(GABA).

Ammoniahypothesis

AmmoniaisproducedintheGItractbybacterialdegradationofamines,aminoacids,purines,andurea.Normally,ammoniaisdetoxifiedintheliverbyconversiontoureaandglutamine.Inliverdiseaseorportosystemicshunting,portalbloodammoniaisnotconvertedefficientlytourea.Increasedlevelsofammoniamayenterthesystemiccirculationbecauseofportosystemicshunting.

Ammoniahasmultipleneurotoxiceffects,includingalterationofthetransitofaminoacids,water,andelectrolytesacrosstheneuronalmembrane.Ammoniaalsocaninhibitthegenerationofexcitatoryandinhibitorypostsynapticpotentials.Therapeuticstrategiestoreduceserumammonialevelstendtoimprovehepaticencephalopathy.However,approximately10%ofpatientswithsignificantencephalopathyhavenormalserumammonialevels.Furthermore,manypatientswithcirrhosishaveelevatedammonialevelswithoutevidenceofencephalopathy.

Gammaaminobutyricacidhypothesis

GABAisaneuroinhibitorysubstanceproducedintheGItract.ItwaspostulatedthatGABAcrossestheextrapermeablebloodbrainbarriersofpatientswithcirrhosisandtheninteractswithsupersensitivepostsynapticGABAreceptors.[33]Thiswouldleadtothegenerationofinhibitorypostsynapticpotentials.Clinically,thisinteractionwasbelievedtoproducethesymptomsofhepaticencephalopathy.SubsequentworkhassuggestedthatbrainGABAlevelsarenotincreasedinpatientswithcirrhosis.

However,brainlevelsofneurosteroidsareincreasedinpatientswithcirrhosis.[34]TheyarecapableofbindingtotheirreceptorwithintheneuronalGABAreceptorcomplexandcanincreaseinhibitoryneurotransmission.Someinvestigatorscurrentlycontendthatneurosteroidsmayplayakeyroleinhepaticencephalopathy.[35]

Clinicalfeatures

Thesymptomsofhepaticencephalopathymayrangefrommildtosevereandmaybeobservedinasmanyas70%ofpatientswithcirrhosis.Symptomsaregradedonthefollowingscale:

Grade0Subclinicalnormalmentalstatusbutminimalchangesinmemory,concentration,intellectualfunction,coordinationGrade1Mildconfusion,euphoriaordepression,decreasedattention,slowingofabilitytoperformmentaltasks,irritability,disorderofsleeppattern(ie,invertedsleepcycle)Grade2Drowsiness,lethargy,grossdeficitsinabilitytoperformmentaltasks,obviouspersonalitychanges,inappropriatebehavior,intermittentdisorientation(usuallywithregardtotime)Grade3Somnolent,butarousable,stateinabilitytoperformmentaltasksdisorientationwithregardtotimeandplacemarkedconfusionamnesiaoccasionalfitsofragespeechispresentbutincomprehensibleGrade4Coma,withorwithoutresponsetopainfulstimuli

Patientswithmildandmoderatehepaticencephalopathydemonstratedecreasedshorttermmemoryandconcentrationonmentalstatustesting.Findingsonphysicalexaminationincludeasterixisandfetorhepaticus.

Laboratoryabnormalities

Anelevatedarterialorfreevenousserumammonialevelistheclassiclaboratoryabnormalityreportedinpatientswithhepaticencephalopathy.Thisfindingmayaidintheassignmentofacorrectdiagnosistoapatientwithcirrhosiswhopresentswithalteredmentalstatus.

However,serialammoniameasurementsareinferiortoclinicalassessmentingaugingimprovementordeteriorationinpatientsundertherapyforhepaticencephalopathy.Noutilityexistsforcheckingtheammonialevelinapatientwithcirrhosiswhodoesnothavehepaticencephalopathy.

Somepatientswithhepaticencephalopathyhavetheclassic,butnonspecific,electroencephalogram(EEG)changesofhighamplitudelowfrequencywavesandtriphasicwaves.Electroencephalographymaybehelpfulintheinitialworkupofapatientwithcirrhosisandalteredmentalstatus,whenrulingoutseizureactivitymaybenecessary.

CTscanandMRIstudiesofthebrainmaybeimportantinrulingoutintracraniallesionswhenthediagnosisofhepaticencephalopathyisinquestion.

Commonprecipitants

Somepatientswithahistoryofhepaticencephalopathyhavenormalmentalstatuswhenundermedicaltherapy.Othershavechronicmemoryimpairmentinspiteofmedicalmanagement.Bothgroupsofpatientsaresubjecttoepisodesofworsenedencephalopathy.Commonprecipitantsofhyperammonemiaandworseningmentalstatusareasfollows:



DiuretictherapyHypovolemiaRenalfailureGIbleedingInfectionConstipation

Dietaryproteinoverloadisaninfrequentcauseofworseningencephalopathy.Medications,notablyopiates,benzodiazepines,antidepressants,andantipsychoticagents,alsomayworsenencephalopathicsymptoms.

Differentialdiagnosis

Conditionstoconsiderinthedifferentialdiagnosisofencephalopathyincludethefollowing:

IntracraniallesionsEg,subduralhematoma,intracranialbleeding,cerebrovascularaccident,tumor,abscessInfectionsEg,meningitis,encephalitis,abscessMetabolicencephalopathyEg,hypoglycemia,electrolyteimbalance,anoxia,hypercarbia,uremiaHyperammonemiafromothercausesEg,secondarytoureterosigmoidostomy,inheritedureacycledisordersToxicencephalopathyduetoalcoholEg,acuteintoxication,alcoholwithdrawal,WernickeencephalopathyToxicencephalopathyduetodrugsEg,sedativehypnotics,antidepressants,antipsychoticagents,salicylatesOrganicbrainsyndromePostseizureencephalopathy

Management

Nonhepaticcausesofalteredmentalfunctionmustbeexcludedinpatientswithcirrhosiswhohaveworseningmentalfunction.Acheckofthebloodammonialevelmaybehelpfulinsuchpatients.Medicationsthatdepresscentralnervoussystem(CNS)function,especiallybenzodiazepines,shouldbeavoided.Precipitantsofhepaticencephalopathyshouldbecorrected(eg,hypovolemia,metabolicdisturbances,GIbleeding,infection,constipation).

Lactulose

Lactuloseishelpfulinpatientswithanacuteonsetofsevereencephalopathysymptomsandinpatientswithmilder,chronicsymptoms.Thisnonabsorbabledisaccharidestimulatesthepassageofammoniafromtissuesintothegutlumenandinhibitsintestinalammoniaproduction.Initiallactulosedosingis30mLorallyonceortwicedaily.Dosingisincreaseduntilthepatienthas24loosestoolsperday.Dosingshouldbereducedifthepatientcomplainsofdiarrhea,abdominalcramping,orbloating.

Higherdosesoflactulosemaybeadministeredviaeitheranasogastricorrectaltubetohospitalizedpatientswithsevereencephalopathy.Othercathartics,includingcoloniclavagesolutionsthatcontainpolyethyleneglycol(PEG)(eg,GoLytely),alsomaybeeffectiveinpatientswithsevereencephalopathy.

Inastudy,Sharmaetalconcludedthattheuseoflactuloseeffectivelypreventshepaticencephalopathyrecurrenceincirrhosis.Patientswithcirrhosisrecoveringfromhepaticencephalopathywererandomizedtoreceivelactulose(n=61)orplacebo(n=64).Overamedianfollowupof14months,12patients(19.6%)inthelactulosegroupdevelopedhepaticencephalopathy,comparedwith30patients(46.8%)intheplacebogroup.[36]

Antibiotics

Neomycinandotherantibiotics(eg,metronidazole,oralvancomycin,paromomycin,oralquinolones)serveassecondlineagents.Theyworkbydecreasingthecolonicconcentrationofammoniagenicbacteria.Neomycindosingis2501000mgorally24timesdaily.Treatmentwithneomycinmaybecomplicatedbyototoxicityandnephrotoxicity.

Rifaximin(Xifaxan,SalixPharmaceuticals,Inc,Morrisville,NC)isanonabsorbableantibioticthatreceivedFDAapprovalin2004forthetreatmentoftravelers'diarrheaandwasgivenapprovalin2010forthereductionofrecurrenthepaticencephalopathy.Itsuseisalsobeingstudiedinirritablebowelsyndrome.DatafromEuropesuggestthatrifaximincandecreasecoloniclevelsofammoniagenicbacteria,withresultingimprovementinthesymptomsofhepaticencephalopathy.

Adoubleblind,placebocontrolledtrial,indicatedthatrifaximincanpreventtheoccurrencehepaticencephalopathy.Inthestudy,299patientswhoserecurrenthepaticencephalopathywasinremissionreceivedeitherrifaximin550mgorplacebotwicedaily.Eachgroupalsoreceivedlactulose.Breakthroughepisodesofhepaticencephalopathyoccurredin22%ofpatientstreatedwithrifaximinandin46%ofpatientswhoweregivenplacebo,whilehepaticencephalopathyrelatedhospitalizationoccurredin14%ofrifaximinpatientsandin23%ofplacebopatients.[37]Rifaximinalsoappearedtobemoreeffectivethanlactuloseintrialsthatcomparedthe2drugsheadtohead.[38]

Otherdrugs

OtherchemicalscapableofdecreasingbloodammonialevelsareLornithineLaspartate(availableinEurope)andsodiumbenzoate.[39]

Proteinrestriction

Lowproteindietswererecommendedroutinelyinthepastforpatientswithcirrhosis.Highlevelsofaromaticaminoacidscontainedinanimalproteinswerebelievedtoleadtoincreasedbloodlevelsofthefalseneurotransmitterstyramineandoctopamine,withresultantworseningofencephalopathicsymptoms.Inthisauthor's



experience,thevastmajorityofpatientscantolerateaproteinrichdiet(>1.2g/kgdaily)thatincludeswellcookedchicken,fish,vegetableprotein,and,ifneeded,proteinsupplements.

Proteinrestrictionisrarelynecessaryinpatientswithsymptomsofchronicencephalopathy.Manypatientswithcirrhosishaveproteincaloriemalnutritionatbaselinetheroutinerestrictionofdietaryproteinintakeincreasestheirriskforworseningmalnutrition.

Intheauthor'sopinion,proteinrestrictionisinfrequentlyvaluableinpatientswithanacuteflareupofsymptomsofhepaticencephalopathy.Onestudyrandomizedhospitalizedpatientswithhepaticencephalopathytoreceiveeitheranormalproteindietoralowproteindiet,inadditiontostandardtreatmentmeasures,andfoundnodifferencebetweenthe2groupsinoutcomesforhepaticencephalopathy.[40]

OtherManifestationsofCirrhosis

Allchronicliverdiseasesthatprogresstocirrhosishaveincommonthehistologicfeaturesofhepaticfibrosisandnodularregeneration.However,patients'signsandsymptomsmayvary,dependingontheunderlyingetiologyofthedisease.

Asanexample,patientswithendstageliverdiseasecausedbyhepatitisCmaydevelopprofoundmusclewasting,markedascites,andseverehepaticencephalopathy,withonlymildjaundice.Incontrast,patientswithendstageprimarybiliarycirrhosismaybedeeplyicteric,withnoevidenceofmusclewasting.Thesepatientsmaycomplainofextremefatigueandpruritusandhavenocomplicationsofportalhypertension.Inbothcases,medicalmanagementisfocusedonthereliefofsymptoms.Livertransplantationshouldbeconsideredasapotentialtherapeuticoption,giventheinexorablecourseofmostcasesofendstageliverdisease.

Manypatientswithcirrhosisexperiencefatigue,anorexia,weightloss,andmusclewasting.Cutaneousmanifestationsofcirrhosisincludejaundice,spiderangiomata,skintelangiectasias(termed"papermoneyskin"byDameSheilaSherlock),palmarerythema,whitenails,disappearanceoflunulae,andfingerclubbing,especiallyinthesettingofhepatopulmonarysyndrome.

Patientswithcirrhosismayexperienceincreasedconversionofandrogenicsteroidsintoestrogensinskin,adiposetissue,muscle,andbone.Malesmaydevelopgynecomastiaandimpotence.Lossofaxillaryandpubichairisnotedinmenandwomen.Hyperestrogenemiaalsomayexplainspiderangiomataandpalmarerythema.

Hematologicmanifestations

Anemiamayresultfromfolatedeficiency,hemolysis,orhypersplenism.[41]Thrombocytopeniausuallyissecondarytohypersplenismanddecreasedlevelsofthrombopoietin.Coagulopathyresultsfromdecreasedhepaticproductionofcoagulationfactors.Ifcholestasisispresent,decreasedmicelleentryintothesmallintestineleadstodecreasedvitaminKabsorption,withresultingreductioninhepaticproductionoffactorsII,VII,IX,andX.Patientswithcirrhosisalsomayexperiencefibrinolysisanddisseminatedintravascularcoagulation.

Pulmonaryandcardiacmanifestations

Patientswithcirrhosismayhaveimpairedpulmonaryfunction.Pleuraleffusionsandthediaphragmaticelevationcausedbymassiveascitesmayalterventilationperfusionrelations.Interstitialedemaordilatedprecapillarypulmonaryvesselsmayreducepulmonarydiffusingcapacity.

Patientsalsomayhavehepatopulmonarysyndrome(HPS).Inthiscondition,pulmonaryarteriovenousanastomosesresultinarteriovenousshunting.HPSisapotentiallyprogressiveandlifethreateningcomplicationofcirrhosis.ClassicHPSismarkedbythesymptomofplatypneaandthefindingoforthodeoxia,butthesyndromemustbeconsideredinanypatientwithcirrhosiswhohasevidenceofoxygendesaturation.

HPSisdetectedmostreadilybyechocardiographicvisualizationoflateappearingbubblesintheleftatriumfollowingtheinjectionofagitatedsaline.PatientscanreceiveadiagnosisofHPSwhentheirPaO2islessthan70mmHg.SomecasesofHPSmaybecorrectedbylivertransplantation.Infact,apatient'scoursetolivertransplantationmaybeexpeditedwhenhisorherPaO2islessthan60mmHg.

Portopulmonaryhypertension(PPHTN)isobservedinupto6%ofpatientswithcirrhosis.Itsetiologyisunknown.PPHTNisdefinedasthepresenceofameanpulmonaryarterypressureofgreaterthan25mmHginthesettingofanormalpulmonarycapillarywedgepressure.

RoutineDopplerechocardiographyisperformedaspartofmanylivertransplantprogramstoruleouttheintervaldevelopmentofPPHTNinpatientsonthetransplantwaitinglist.Indeed,thepresenceofameanpulmonarypressureofgreaterthan35mmHgsignificantlyincreasestherisksoflivertransplantsurgery.PatientswhodevelopseverePPHTNmayrequireaggressivemedicaltherapyinanefforttostabilizepulmonaryarterypressuresandtodecreasetheirchanceofperioperativemortality.

Hepatocellularcarcinomaandcholangiocarcinoma

Hepatocellularcarcinoma(HCC)ultimatelyarisesin1025%ofpatientswithcirrhosisintheUnitedStates.Ittypicallyoccursinaboutof3%ofpatientsperyear,whentheetiologyofcirrhosisishepatitisB,hepatitisC,oralcohol.Itdevelopsmorecommonlyinpatientswithunderlyinghereditaryhemochromatosisoralpha1antitrypsindeficiency.HCCisobservedlesscommonlyinprimarybiliarycirrhosisandisararecomplicationofWilsondisease.

Cholangiocarcinomaoccursinapproximately10%ofpatientswithprimary



sclerosingcholangitis.EarlydiagnosisofHCCiscriticalbecauseitispotentiallycurablethrougheitherliverresectionorlivertransplant.

Otherdiseases

Otherconditionsthatappearwithincreasedincidenceinpatientswithcirrhosisincludepepticulcerdisease,diabetes,andgallstones.

AssessmentoftheSeverityofCirrhosis

Formanyyears,themostcommonprognostictoolusedinpatientswithcirrhosiswastheChildTurcottePugh(CTP)system.ChildandTurcottefirstintroducedtheirscoringsystemin1964asameansofpredictingtheoperativemortalityassociatedwithportocavalshuntsurgery.Pugh'srevisedsystemin1973substitutedalbuminforthelessspecificvariableofnutritionalstatus.[42]SubsequentrevisionshaveusedtheInternationalNormalizedRatio(INR)inadditiontoprothrombintime.

EpidemiologicworkshowsthattheCTPscoremaypredictlifeexpectancyinpatientswithadvancedcirrhosis.ACTPscoreof10orgreaterisassociatedwitha50%chanceofdeathwithin1year.(SeeTable4,below.)

Table4.ChildTurcottePughScoringSystemforCirrhosis(OpenTableinanewwindow)

ClinicalVariable 1Point 2Points 3Points

Encephalopathy None Grade12 Grade34

Ascites Absent Slight Moderateorlarge

Bilirubin(mg/dL) 3

BilirubininPBC*orPSC**(mg/dL) 3.5 2.83.5



Cholestyramineisthemainstayoftherapyforthepruritusofliverdisease.ToavoidcompromisingGIabsorption,careshouldbetakentoavoidcoadministrationofthisorganicanionbinderwithanyothermedication.

Othermedicationsthatmayprovidereliefagainstpruritusincludeantihistamines(eg,diphenhydramine,hydroxyzine),ursodeoxycholicacid,ammoniumlactate12%skincream(LacHydrin,WestwoodSquibbPharmaceuticals,Inc,Princeton,NJ),doxepin,andrifampin.Naltrexone,anopiate(anopioidantagonist),maybeeffectivebutisoftenpoorlytolerated.Gabapentinisanunreliabletherapy.Patientswithseverepruritusmayrequireinstitutionofultravioletlighttherapyorplasmapheresis.

Hypogonadism

Somemalepatientssufferfromhypogonadism.Patientswithseveresymptomsmayundergotherapywithtopicaltestosteronepreparations,althoughtheirsafetyandefficacyisnotwellstudied.Similarly,theutilityandsafetyofgrowthhormonetherapyremainsunclear.

Osteoporosis

Patientswithcirrhosismaydeveloposteoporosis.SupplementationwithcalciumandvitaminDisimportantinpatientsathighriskforosteoporosis,especiallypatientswithchroniccholestasisorprimarybiliarycirrhosisandpatientsreceivingcorticosteroidsforautoimmunehepatitis.Thediscoveryonbonedensitometrystudiesofdecreasedbonemineralizationmayprompttheinstitutionoftherapywithanaminobisphosphonate(eg,alendronatesodium).

Vaccination

PatientswithchronicliverdiseaseshouldreceivevaccinationtoprotectthemagainsthepatitisA.Otherprotectivemeasuresincludevaccinationagainstinfluenzaandpneumococci.

Drughepatotoxicityinthepatientwithcirrhosis

Theinstitutionofanynewmedicaltherapywarrantstheperformanceofmorefrequentliverchemistriespatientswithliverdiseasecanillaffordtohavedruginducedliverdiseasesuperimposedontheircondition.Medicationsassociatedwithdruginducedliverdiseaseincludethefollowing:

Nonsteroidalantiinflammatorydrugs(NSAIDs)IsoniazidValproicacidErythromycinAmoxicillinclavulanateKetoconazoleChlorpromazineEzetimibe

Statins

Hepatic3methylglutarylcoenzymeA(HMGCoA)reductaseinhibitorsarefrequentlyassociatedwithmildelevationsofalanineaminotransferase(ALT)levels.However,severehepatotoxicityisreportedinfrequently.[45]Theliteraturesuggeststhatstatinscanbeusedsafelyinmostpatientswithchronicliverdisease.[46]Certainly,liverchemistriesshouldbefollowedfrequentlyaftertheinitiationoftherapy.

Inastudyoftheeffectsofstatinsin58patientswithprimarybiliarycirrhosis,RajabandKaplanconcludedthatstatinuseissafeinpatientswiththiscondition.[47]Individualsinthestudywereonstatinsforamedianperiodof41months,withALTlevelsmeasuredevery3months.Theauthorsfoundthattheselevelsdidnotincrease,beingslightlyelevatedwhenstatintreatmentbeganandnormalbythelastfollowupanalysis.Patientsdidnotcomplainofmusclepainorweakness,andserumcholesterollevelsfellby30%.

Analgesics

Theuseofanalgesicsinpatientswithcirrhosiscanbeproblematic.Althoughhighdoseacetaminophenisawellknownhepatotoxin,mosthepatologistspermittheuseofacetaminopheninpatientswithcirrhosisatdosesofupto2000mgdaily.

NSAIDusemaypredisposepatientswithcirrhosistodevelopGIbleeding.PatientswithdecompensatedcirrhosisareatriskforNSAIDinducedrenalinsufficiency,presumablybecauseofprostaglandininhibitionandworseningofrenalbloodflow.Opiateanalgesicsarenotcontraindicatedbutmustbeusedwithcautioninpatientswithpreexistinghepaticencephalopathyonaccountofthedrugs'potentialtoworsenunderlyingmentalfunction.

Otherdrugs

Aminoglycosideantibioticsareconsideredobligatenephrotoxinsinpatientswithcirrhosisandshouldbeavoided.Lowdoseestrogensandprogesteroneappeartobesafeinthesettingofliverdisease.

AreviewbyLewisandStineprovidedrecommendations,includingthefollowing,onthesafeuseofmedicationsinpatientswithcirrhosis[48,49]:

Lowermedicationdosesshouldgenerallybeused,particularlyinpatientswithsignificantliverdysfunctionProtonpumpinhibitorsandhistamine2blockersshouldbeusedonlyforvalidindications,sincetheymayleadtoseriousinfectionsinpatientswithcirrhosis

NutritionandExercise



Manypatientscomplainofanorexia,whichmaybecompoundedbythedirectcompressionofascitesontheGItract.Careshouldbetakentoensurethatpatientsreceiveadequatecaloriesandproteinintheirdiets.Patientsfrequentlybenefitfromtheadditionofcommonlyavailableliquidandpowderednutritionalsupplementstothediet.Onlyrarelycanpatientsnottolerateproteinsintheformofchicken,fish,vegetables,andnutritionalsupplements.Institutionofalowproteindietoutofconcernthathepaticencephalopathymaydevelopplacesthepatientatriskforprofoundmusclewasting.

The2010practiceguidelinesforalcoholicliverdiseasepublishedbytheAmericanAssociationfortheStudyofLiverDiseasesandtheAmericanCollegeofGastroenterologyrecommendaggressivetreatmentofproteincaloriemalnutritioninpatientswithalcoholiccirrhosis.Multiplefeedingsperday,includingbreakfastandasnackatnight,arespecified.[50]

Regularexercise,includingwalkingandevenswimming,shouldbeencouragedinpatientswithcirrhosis,topreventthesepatientsfromslippingintoaviciouscycleofinactivityandmusclewasting.Debilitatedpatientsfrequentlybenefitfromaformalexerciseprogramsupervisedbyaphysicaltherapist.

SurgicalRisks

Surgeryandgeneralanesthesiacarryincreasedrisksinthepatientwithcirrhosis.Anesthesiareducescardiacoutput,inducessplanchnicvasodilation,andcausesa3050%reductioninhepaticbloodflow.Thisplacesthecirrhoticliveratadditionalriskfordecompensation.

Surgeryissaidtobesafeinthesettingofmildchronichepatitis.Itsriskinpatientswithseverechronichepatitisisunknown.Patientswithwellcompensatedcirrhosishaveincreased,butacceptable,morbidityandmortalityrisks.Careshouldbetakentoavoidpostoperativeinfection,fluidoverload,unnecessarysedativesandanalgesics,andpotentiallyhepatotoxicandnephrotoxicdrugs(eg,aminoglycosideantibiotics).

Intheprelaparoscopicera,astudyofnonshuntabdominalsurgeriesdemonstrateda10%mortalityrateforpatientswithChildClassAcirrhosis,asopposedtoa30%mortalityrateforpatientswithChildClassBcirrhosisanda75%mortalityrateforpatientswithChildClassCcirrhosis.[51]Althoughcholecystectomywasamongtheriskiersurgeriesnoted,severalreportshavedescribedthesuccessfulperformanceoflaparoscopiccholecystectomyinpatientswithChildClassAorBcirrhosis.[52]

StudieshaveusedtheMELDscoreasatoolinpredictingpostoperativeoutcomesinabdominalsurgery(seetheMELDScorecalculator).Inonestudy,apreoperativeMELDscoreofgreaterthan14wasabetterpredictorofpostoperativedeaththanChildClassCstatus.[53]

Inastudyofpatientswithcirrhosiswhounderwentmajordigestive,orthopedic,orcardiovascularsurgery,thepreoperativeMELDscoresandtheirassociated30daypostoperativemortalityrateswereasfollows[54]:

MELDscoreof7orless5.7%mortalityMELDscoreof81110.3%mortalityMELDscoreof121525.4%mortalityMELDscoreof162044%mortalityMELDscoreof212553.8%mortalityMELDscoreofgreaterthan2690%mortality

Thebenefitsandtherisksofsurgeryshouldbecarefullyweighedbeforeadvisingthepatientwithcirrhosistoundergosurgery.

LiverTransplantation

Livertransplantationhasemergedasanimportantstrategyinthemanagementofpatientswithdecompensatedcirrhosis.Patientsshouldbereferredforconsiderationoflivertransplantationafterthefirstsignsofhepaticdecompensation.

Advancesinsurgicaltechnique,organpreservation,andimmunosuppressionhaveresultedindramaticimprovementsinpostoperativesurvival.Intheearly1980s,thepercentageofpatientssurviving1yearand5yearsafterlivertransplantwereonly70%and15%,respectively.Now,patientscananticipatea1yearsurvivalrateof8590%anda5yearsurvivalrateofhigherthan70%.Qualityoflifeafterlivertransplantisgoodorexcellentinmostcases.

Contraindicationstotransplant

Contraindicationsforlivertransplantationincludeseverecardiovascularorpulmonarydisease,activedrugoralcoholabuse,malignancyoutsidetheliver,sepsis,orpsychosocialproblemsthatmightjeopardizepatients'abilitiestofollowtheirmedicalregimensaftertransplant.

Accordingtothe2010guidelinesforalcoholicliverdiseasefromtheAmericanAssociationfortheStudyofLiverDiseases,patientswhoseendstageliverdiseaseisalcoholrelatedshouldbeconsideredascandidatesfortransplantationafteramedicalandpsychosocialevaluationthatincludesformalassessmentoftheprobabilityoflongtermabstinence.[50]

Thepresenceofthehumanimmunodeficiencyvirus(HIV)inthebloodstreamalsoisacontraindicationtotransplant.However,successfullivertransplantationsarenowbeingperformedinpatientswithnodetectableHIVviralloadduetoantiretroviraltherapy.[55]Additionalclinicalstudyisrequiredbeforelivertransplantationcanbeofferedroutinelytosuchpatients.

Organallocation



Approximately6500livertransplantsareperformedintheUnitedStateseachyear.Anincreasingnumberoflivesaresavedeachyearbytransplant.However,thenumberofdiagnosedcasesofcirrhosisisrising,fueledinpartbythehepatitisCepidemicandbythegrowingnumberofcasesofnonalcoholicfattyliverdisease(NAFLD).Thishasresultedinadramaticincreaseinthenumberofpatientslistedascandidatesforlivertransplantation.

Approximately1215%ofpatientslistedascandidatesdiewhilewaitingbecauseoftherelativelystaticnumberoforgandonations.Strategiestoimprovethecurrentdonororganshortageincludeprogramstoincreasepublicawarenessoftheimportanceoforgandonation,increaseduseoflivingdonorlivertransplantationforpediatricandadultrecipients,organdonationaftercardiacdeath,andtheuseofextendedcriteriadonors(ECDs).

AnECD"deviatesinsomeaspectfromtheidealdonor."OneexampleofanECDorganisthehepatitisCinfectedliverwithminimalfibrosisthatistransplantedintoahepatitisCinfectedrecipient.Suchtransplantshavebeenperformedsuccessfullyforanumberofyears.OtherexamplesofECDsincludedonorsolderthan70yearsanddonorswithrelativelyfattylivers.

TheneedforamoreefficientandequitablesystemoforganallocationresultedindramaticchangesinUnitedStatesorganallocationpolicyin2002.[56]Previously,patientswhowereacceptedaslivertransplantcandidateswith79CTPpoints(ChildClassB)receivedlowpriorityonthetransplantwaitinglistmaintainedbytheUnitedNetworkforOrganSharing(UNOS).Patientswith10ormoreCTPpoints(ChildClassC)receivedahigherpriority.EmergentlivertransplantationatUNOSstatus1wasreservedprimarilyfornoncirrhoticpatientssufferingfromfulminanthepaticfailure.

Since2002,liversfromdeceaseddonors(ie,cadavericorgans)havebeenallocatedtocirrhoticpatientsusingtheMELDscoringsystemandthePediatricEndStageLiverDisease(PELD)scoringsystem[43](seetheMELDScorecalculatorandthePELDScorecalculator).

IntheMELDscoringsystemforadults,apatientreceivesascorebasedonthefollowingformula:

MELDscore=0.957xLoge(creatininemg/dL)+0.378xLoge(bilirubinmg/dL)+1.120xLoge(INR)+0.643

Asanexample,acirrhoticpatientwithacreatininelevelof1.9mg/dL,abilirubinlevelof4.2mg/dL,andanINRof1.2wouldreceivethefollowingscore:

MELDscore=(0.957xLoge1.9)+(0.378xLoge4.2)+(1.120xLoge1.2)+0.643=2.039

Thatvalueisthenmultipliedby10togivethepatientariskscoreof20.Patients'MELDscoresarerecalculatedeverytimetheyundergolaboratorytesting.PatientsmaybeassignedamaximumMELDscoreof40points.

ThePELDsystemusesasomewhatdifferentformula:PELDscore=0.480xLoge(totalbilirubinmg/dL)+1.857xLoge(INR)0.687xLoge(albuming/dL)+0.436ifthepatientisyoungerthan1year+0.667ifthepatienthasgrowthfailure(



Theshortageofdonororganshasspurredinterestintheuseofliverallograftsfromnonheartbeatingdonors(NHBDs).Typically,anNHBDisanindividualwhohassustainedirreversibleneurologicdamagebutwhoseclinicalconditiondoesnotmeetformalbraindeathcriteria.Knowingthis,aprospectivedonor'sfamilywillgiveconsentforwithdrawalofcareandfororgandonation.Thedonoristhenbroughttotheoperatingroom,withtheanticipationthatwithdrawalofventilatorsupportwillresultinthecessationofthepatient'scardiopulmonaryfunction.Oncedeathisdeclared,organprocurementsurgerycanproceed.

Incontrasttotheorganprocuredfromaheartbeatingdonor(HBD),theallograftobtainedfromanNHBDmaybesubjecttoconsiderablewarmischemiatimebeforeitisperfusedwithcoldpreservativesolution.

Areviewcomparingtheresultsoflivertransplantationusingallograftsfrom144NHBDsand26,856HBDsoveran8yearperiodfoundbetteroutcomesinHBDtransplantrecipients.[58]Oneand3yeargraftsurvivalrateswere70%and63%,respectively,withorgansfromNHBDs,asopposedto80%and72%,respectively,withorgansfromHBDs.HigherratesofprimarynonfunctionandretransplantationwereseenintherecipientsofallograftsfromNHBDs.

Otherauthorshavedescribedahigherincidenceofhepaticarterystenosis,hepaticabscesses,andbilomasintherecipientsofallograftsfromNHBDs.[59]Itispossiblethatimprovedresultswillbeseenbylimitingdonorage,byminimizingdonorwarmischemiatime,andbynotattemptingtotransplantliversfromNHBDsintorecipientswhoareseverelyill.

Thefutureoflivertransplantation

Excitingnewtechnicaladvancesalsomayhelptoimprovepatients'chancesofsurvival.Inthefuture,expandeduseofhepatocytetransplantationmayoccur.Inthistherapy,asplenicarterycatheterisusedtodeliverbillionsofcryopreservedhepatocytesintothespleenofapatientwhohasendstageliverdisease.Thepatientthenundergoesroutineimmunosuppression.Thisstrategyhasbeenemployedsuccessfullyinasmallnumberofpatientswithcirrhosisandfulminanthepaticfailure(FHF)whowerenotcandidatesforlivertransplantsurgery.

BioartificialliversmayseeincreasedapplicationinthecareofpatientswithFHFand,perhaps,cirrhosis.The2moststudieddevicesarecomposedofsemipermeablecapillaryhollowfibermembranesenclosedinaplasticshell.EitherhumanC3Ahepatomacellsorpighepatocytesareattachedtotheexteriorsurfaceofthemembranesasbloodfromthepatientispumpedthroughthedevice.IntracranialpressureandhepaticencephalopathyimprovedinsomepatientswithFHFwhowereassistedwiththesedevices.However,currentlyavailablebioartificiallivershavenotyetfulfilledthegoalsofbiotransformingandremovingtoxinswhilesupplyingthepatientwithclottingfactorsandgrowthfactors.

Xenotransplantationmaycomeintouseduringthenextdecade.Todate,allattemptsatxenotransplantationinhumanshavesufferedfromsevere,earlyhumoralorlatecellularrejectionandhaveresultedinpatientdeath.Advancesingeneticengineeringmayleadtothedevelopmentofswinewhoseliversaremorelikelytoundergograftacceptancewhentransplantedintohumans.Oncethisobstacleisovercome,adeterminationcanbemadeastowhetheraswineliverisaneffectivesubstituteforahumanliver.

Mostimportantly,themedicalworldawaitsthedevelopmentofmedicaltherapiesthatforestallthedevelopmentofhepaticfibrosislongbeforepatientsdevelopcirrhosisanditscomplications.

PatientMonitoring

Patientswithcirrhosisshouldundergoroutinefollowupmonitoringoftheircompletebloodcount,renalandliverchemistries,andprothrombintime.Theauthor'spolicyistomonitorstablepatients34timesperyear.

Surveillanceofesophagealvarices

Theauthorperformsroutinediagnosticendoscopytodeterminewhetherthepatienthasasymptomaticesophagealvarices.Followupendoscopyisperformedin2yearsifvaricesarenotpresent.Ifvaricesarepresent,treatmentisinitiatedwithanonselectivebetablocker(eg,propranolol,nadolol),aimingfora25%reductioninheartrate.Suchtherapyofferseffectiveprimaryprophylaxisagainstnewonsetofvaricealbleeding.[60]Patientswithlargeesophagealvaricesshouldundergoprophylacticendoscopicvaricealligation.

Surveillanceforhepatocellularcarcinoma

Theincidenceofhepatocellularcarcinoma(HCC)hasrisenintheUnitedStates.ThepracticeguidelinesoftheAmericanAssociationfortheStudyofLiverDiseasesrecommendthatpatientswithcirrhosisundergosurveillanceforHCCwithultrasonographyevery6months.[61]Thediscoveryofalivernoduleshouldprompttheperformanceofa4phaseCTscanoranMRIscan(ie,unenhanced,arterial,venous,anddelayedphases).Lesionsthatenhanceinthearterialphaseandexhibit"washout"inthedelayedphasesarehighlysuggestiveofHCC.

ManyauthorscontendthatthecombinationofarterialenhancementandwashoutonCTscanningorMRIoffersgreaterdiagnosticpowerforHCCthandoesguidedliverbiopsy.[62,63]Indeed,guidedliverbiopsieshavea2030%falsenegativerateinmakingthediagnosisofHCC.CurrentguidelinessupporttheuseofCTscanningandMRIinconfirmingthepresenceofHCC.BiopsyisnotrequiredinordertodefinealesionasHCC.[61]However,CTscanningorultrasonographicallyguidedliverbiopsymaybeusefulwhenanodulesenhancementcharacteristicsarenottypicalforHCC.

PatientswithadiagnosisofHCCandnoevidenceofextrahepaticdisease,as



determinedbychestandabdominalCTscansandbybonescan,shouldbeofferedcurativetherapy.Commonly,thistherapyentailsliverresectionsurgeryforpatientswithChildClassAcirrhosisandanacceleratedcoursetolivertransplantationforpatientswithChildClassBorCcirrhosis.

Patientswhoareawaitinglivertransplantationareoftenofferedminimallyinvasivetherapiesinanefforttokeeptumorsfromspreading.Thesetherapiesincludepercutaneousinjectiontherapywithethanol,radiofrequencyandmicrowavethermalablation,chemoembolization,intensitymodulatedradiationtherapy,andradioembolization.

ContributorInformationandDisclosures

AuthorDavidCWolf,MD,FACP,FACG,AGAF,FAASLDMedicalDirectorofLiverTransplantation,WestchesterMedicalCenterProfessorofClinicalMedicine,DivisionofGastroenterologyandHepatobiliaryDiseases,DepartmentofMedicine,NewYorkMedicalCollege

DavidCWolf,MD,FACP,FACG,AGAF,FAASLDisamemberofthefollowingmedicalsocieties:AmericanAssociationfortheStudyofLiverDiseases,AmericanCollegeofGastroenterology,AmericanCollegeofPhysicians,AmericanGastroenterologicalAssociation

Disclosure:ReceivedconsultingfeefromSalixforspeakingandteachingReceivedgrant/researchfundsfromIkariaforotherReceivedgrant/researchfundsfromVitalTherapiesforotherReceivedconsultingfeefromGileadforspeakingandteachingReceivedconsultingfeefromAbbvieforspeakingandteaching.

ChiefEditorBSAnand,MDProfessor,DepartmentofInternalMedicine,DivisionofGastroenterology,BaylorCollegeofMedicine

BSAnand,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationfortheStudyofLiverDiseases,AmericanCollegeofGastroenterology,AmericanGastroenterologicalAssociation,AmericanSocietyforGastrointestinalEndoscopy

Disclosure:Nothingtodisclose.

AcknowledgementsBSAnand,MDProfessor,DepartmentofInternalMedicine,DivisionofGastroenterology,BaylorCollegeofMedicine

BSAnand,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationfortheStudyofLiverDiseases,AmericanCollegeofGastroenterology,AmericanGastroenterologicalAssociation,andAmericanSocietyforGastrointestinalEndoscopy

Disclosure:Nothingtodisclose.

FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollegeofPharmacyEditorinChief,MedscapeDrugReference

Disclosure:MedscapeSalaryEmployment

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