3/5/2017 Cysticfibrosis:HepatobiliarydiseaseUpToDate

OfficialreprintfromUpToDate
www.uptodate.com2017UpToDate

Cysticfibrosis:Hepatobiliarydisease

Authors: DanielHLeung,MD,DrucyBorowitz,MD
SectionEditors: GeorgeBMallory,MD,ElizabethBRand,MD
DeputyEditor: AlisonGHoppin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2017.|Thistopiclastupdated:Oct12,2015.

INTRODUCTIONCysticfibrosisrelatedliverdisease(CFLD)isbecomingincreasinglyrecognized
duetoearlydiagnosisofcysticfibrosis(CF),improvedlifeexpectancy,andmorevigilantscreeningand
monitoringbyCFproviders.PatientswithsevereCFLDusuallypresentduringchildhood,andthe
diseasetendstoprogressrapidly.MilderformsofCFLDcanbedifficulttodiagnosebecausepatients
mayremainasymptomaticuntillateinthediseaseprocess,andcurrentlyavailablescreeningtests
correlatepoorlywithdiseaseseverity.EarlyidentificationofCFLDpermitsanticipationandtreatmentof
itscomplications,whichincludemalnutrition,varicealbleedingduetoportalhypertension,and
occasionallyliverfailure.OtherhepatobiliarycomplicationsofCFincludecholelithiasis(gallstones),
cholecystitis,andmicrogallbladder.

Theclinicalmanifestations,diagnosis,andmanagementofCFLDwillbediscussedinthistopicreview,
andassociateddisordersofthegallbladderwillbediscussedbriefly.Othertopicreviewsrelevanttothe
managementofapatientwithCFandhepatobiliarydiseaseinclude:

(See"Cysticfibrosis:Overviewofgastrointestinaldisease".)
(See"Cysticfibrosisrelateddiabetesmellitus".)
(See"Cysticfibrosis:Clinicalmanifestationsanddiagnosis".)
(See"Cysticfibrosis:Nutritionalissues".)
(See"Cysticfibrosis:Assessmentandmanagementofpancreaticinsufficiency".)
(See"Cysticfibrosis:Overviewofthetreatmentoflungdisease".)

EPIDEMIOLOGYANDNATURALHISTORYThetermCFrelatedliverdisease(CFLD)hasbeen
usedtodescribeawiderangeofmanifestations,fromcommonbutinconsequentialelevationsof
transaminasestocirrhosiswithportalhypertension.ThemostsevereformofCFLD,biliarycirrhosis,
oftenhasonsetduringthefirstdecadeoflifeandtendstoprogressrapidly[1].Duringthefirsttwo
yearsoflife,upto50percentofindividualswithCFhaveelevationsofaminotransferaseactivityand
thismaybetransient[2,3].

MildformsofCFLDarecommonandaregenerallyasymptomatic.CFLDisprevalentinstudiesthat
usesystematictechniquesandincludeaspartofthedefinitionofCFLD,"elevationoftransaminaseson
atleasttwoconsecutivemeasurements."Asexamples,intwoseriesofpediatricpatientswithCFwho
underwentrigorousscreening,30to40percentexhibitedsomeevidenceofCFLD,withmostcases
diagnosedwithinthefirst12yearsoflife,basedontransaminaseelevations[4,5].Inautopsystudies
thatwereperformedbeforethemoderneraofCFmanagementandoutcome,focalbiliarycirrhosis
andfibrosiswerereportedin10to20percentofpatientswithCFbyoneyearofageandupto80
percentinadultsinmanyofthesepatientstheliverinvolvementisfocal[68].SevereCFLDoccursin
approximately10percentofindividualswithCF,asreportedbyCFregistries[9].

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RiskfactorsforCFLDhistoricallyhaveincludedpresentationwithmeconiumileus(MI),malegender,
pancreaticinsufficiency,Hispanicethnicity,andseveremutationsintheCFtransmembraneregulator
(CFTR)gene,suchastheF508del(deltaF508)mutation.However,alarge,singlecenterstudyof401
CFinfantsovera25yearperiodfoundthattherewasnodifferenceinthepercentageofpatientswith
MIwhodevelopedCFLDversusthosewithout[10]otherstudiesreportedsimilarfindings[11,12].The
discrepancyinriskfactorsmaybedueinparttothelackofconsensusofthedefinitionofCFLD.

Biliarycirrhosiswithportalhypertensionisthemostclinicallyimportantandendstagemanifestationof
CFLD,andiscloselyassociatedwithpooroutcome.Biochemicalorimagingabnormalitieshaveoften
beenusedtoidentifypatientsinearlystagesofdevelopingCFLD.Cluestosignificantliverdisease
includepersistentelevationsgreaterthantwotimestheupperlimitofnormalforaspartate
aminotransferase(AST),alaninetransaminase(ALT),orgammaglutamyltranspeptidase(GGTP),
andthrombocytopeniaorarelativedropinplateletcount.Anultrasoundrevealingabnormal
echogenicity,heterogeneouspattern,ornodularitymaypromptfurtherevaluation.Despiteeffortsby
theCFFoundation(CFF)toconveneinternationalexpertsinCFLDin2007,aconsensusdefinitionof
CFLDforuseinnaturalhistoryandtreatmentstudieshasnotbeendeveloped.

CFLDisassociatedwithCFrelateddiabetes(CFRD),andbothofthesedisordersarepredictorsof
mortality,independentofpulmonaryfunction[13,14].Whilecompensatedcirrhosiscanexistformany
yearsinchildrenand/oradultswithportalhypertension,mostwilldecompensateearlyinlife.Duetothe
demographicsofCFandprogressionoftheassociatedlungdisease,themajorityoflivertransplants
forthisdisorderareperformedinchildren[15].Asanexample,intheUnitedStatesbetween1987and
2009,210childrenoradolescentsunderwentliverorliverlungtransplantationforCFLD,compared
with84adults[16].

PATHOGENESISIntheliver,CFtransmembraneregulator(CFTR)islocatedontheapical
membraneinthebiliaryepithelium,notinthehepatocyte.CFTRisthoughttocontrolwaterandsolute
movementthroughchlorideandbicarbonatesecretion,thuspromotingbileflow.WhenCFTRis
dysfunctional,itcausesthickandtenaciousbilethatcongestsintrahepaticbileducts.Otherfactorsthat
maycontributetothedevelopmentofliverdiseaseinCFincludeimpairedsecretionofmucinsfromthe
submucosalglandsandincreasedglycineconjugatedbileacids.Bothofthesefactorsarethoughtto
contributetothedecreasedflowandincreasedviscosityofthebile.Obstructionofthebiliaryductules
causesthereleaseofproinflammatoryagentsandgrowthfactorsthatinducethesynthesisofcollagen
intheportaltracts,leadingtoprogressivefibrosisandeventuallycirrhosis.Theprogressiontocirrhosis
mayberapidormaytakeyearstodecades[17].Interestingly,mostpatientswithsevereCFrelated
liverdisease(CFLD)donotbecomeclassicallycholestaticorjaundiced,andhepaticsyntheticfunction
usuallyispreserved.

AbnormalitiesofthehepatobiliarysystemoccuralmostsolelyinpatientswithsevereCFTRmutations,
whichleadtotheimpairedsynthesis,modification,orregulationoftheCFTRprotein[18].However,
patientswiththesameCFTRgenotypeareoftendiscordantforCFLDphenotype,suggestingthat
variationingenesotherthanCFTRmaybeanimportantdeterminantofsusceptibility[1].Inparticular,
theSERPINA1ZallelehasbeenassociatedwithanincreasedriskforCFLD,althoughthisaccounts
foronlyasmallpercentageofallpatientswithsevereCFLD.Inaddition,CFrelatedcirrhosisandportal
hypertensionmayaccelerateatanearlyageinthesettingofpulmonaryexacerbations,repeated
infections,ormalnutrition[4].

OtherfactorsthatmaycontributetoCFLDincludemalnutrition,essentialfattyaciddeficiency[19],and
ethanolingestioninolderpatients.Eachofthesefactorscanbeassociatedwithhepaticsteatosis(the
accumulationoffatintheliver),whichmaycauseelevationinlivertransaminases,however,itis

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unclearifhepaticsteatosisprogressestocirrhosisinCFLD.InCFinfantswithmeconiumileus(MI),
exposuretoprolongedparenteralnutritionorahistoryofabdominalsurgerymaycontributetothe
developmentofcholestasis,whichmayresolvewhenfeedingsareresumed.

CLINICALMANIFESTATIONSTherearemultiplepresentationsofliverinvolvementinCF(table1).
Themostclinicallyimportantformisfocalbiliarycirrhosis,whichisoftenprogressiveandleadstoportal
hypertensionandnutritionalissues.Morecommonbutlessclinicallyimportantmanifestationsofliver
diseaseincludeasymptomaticelevationinaminotransferases(upto45percentofindividualswithCF)
andhepaticsteatosis(upto60percentofindividualswithCF)[3].

ProgressiveCFLDAbout40percentofindividualswithCFdevelopclinicallydetectableCFrelated
liverdisease(CFLD)duringchildhoodoradolescence(characterizedbypersistentlyelevated
aminotransferaselevels,hepatomegaly,and/orultrasonographicabnormalities),andabout20percent
ofthese(5to10percentofindividualswithCF)goontodevelopcirrhosis[5].Severalcaseseriesthat
useduniversalscreeningproceduresdemonstratedthatsevereCFLDusuallydevelopsduring
childhoodoradolescence,withnoincidentcasesbeyondtheageof18years[3,5].Similarly,theCF
Foundation(CFF)dataregistryreportsapproximatelyequalpercentagesofpatientswithCFLD(and
specificmanifestationsthereof,suchasvarices)inthe<18and>18agegroups,suggestingthatmost
casespresentbeforeage18[9].However,itispossiblethatwithincreasinglifeexpectancy,more
caseswillbeidentifiedofslowlyprogressiveCFLDthatevolvestosymptomaticportalhypertension,
andanincreasingproportionofindividualswithcompensatedpediatricCFLDwillbetransplantedas
adults.

Liverinvolvementusuallycomestoattentionwhenroutinescreeninginanasymptomaticpatient
revealsabnormalliverenzymes,includingaspartateaminotransferase(AST),alanine
aminotransferase(ALT),gammaglutamyltranspeptidase(GGTP),and/oralkalinephosphatase.Some
individualshaveevidenceofportalhypertensionatpresentationorasthediseaseprogresses,
characterizedbysplenomegaly,whichresultsinsplenicsequestrationandthereforedecreasedplatelet
countintheperipheralblood.Serumbilirubinlevelsaregenerallynotelevateduntillateinthedisease
course,asistypicalforcirrhosis.ScreeningforanddiagnosisofprogressiveCFLDarediscussed
below.(See'Evaluation'below.)

Patientswithcirrhosisandportalhypertensionhaveassociatedrisksforvaricealhemorrhage[20,21].
Mostremaininastateofcompensatedcirrhosisforyearsordecades.Eventually,someprogressto
decompensatedcirrhosis,heraldedbyascites,liverfailurewithsyntheticdysfunction(coagulopathy
andhypoalbuminemia),orhepaticencephalopathy.Cutaneousmanifestationssuchasjaundice,
palmarerythema,andspiderhemangiomatadeveloplateinthediseasecourse.

Histologically,CFLDischaracterizedbyproliferationofthebileductsandportalfibrosis,with
accumulationofamorphouspinkmaterialwithinthebileductswhenstainedwithperiodicacidSchiff
(PAS)stain(picture1).Intheearlierphases,thelesionsmayhaveapatchydistribution,whichhas
beentermed"focalbiliarycirrhosis"inautopsystudies.Withdiseaseprogression,cirrhosisdevelops,
characterized(asinotherformsofcirrhosis)bythedevelopmentofcollagenousbridgesbetween
nearlyallportalandcentralvenousareas,encirclingnodulesofvaryingsizes(picture2)[35].

Othermanifestationsofliverdisease

NeonatalcholestasisFewerthan10percentofinfantswithCFdevelopcholestaticliverdisease
duringtheneonatalperiod.Thosewhodopresentininfancypresentwithprolongedconjugated
hyperbilirubinemia.Rarely,biliaryobstructioncanbeverysevereduringinfancy,mimickingbiliary
atresia(picture3)[22,23](see"Causesofcholestasisinneonatesandyounginfants").The

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hepatomegalyandcholestasistendtoregressduringthefirstfewmonthsoflifewithimprovementsin
nutrition,andthispresentationdoesnotpredictlatercirrhosis[10,24].Similarly,isolatedelevationsin
aminotransferaseactivitypriortotwoyearsofageareoftentransientandgenerallydonotpredictlater
CFLD[2,3].

HepaticsteatosisHepaticsteatosisisthemostcommonlyobservedpathologicabnormalityin
CFLD(picture4)andcanbefoundinupto60percentofindividualswithCF,withawiderangein
prevalencedependingonthepatientpopulationandmethodsusedtodeterminesteatosis[3,25,26].
Thesonographicorhistologicfindingofsteatosisissometimesattributedtoiatrogenicorenvironmental
factors,particularlymalnutritionandessentialfattyaciddeficiency[19](see'Pathogenesis'above).The
relationshipbetweenhepaticsteatosisandthedevelopmentoffocalbiliarycirrhosisinCFisunclear.
SteatosisisthoughttobeabenignfindingamongchildrenwithCF.Eveninseverecases,inwhichthe
steatosisbecomespanacinarormorewidespread,inflammationandotherfeaturesofsteatohepatitis
generallyareabsent[27,28].

EVALUATIONThegoaloftheevaluationistodetectprogressiveCFrelatedliverdisease(CFLD)
anddistinguishitfromotherliverabnormalitiesthatarerelativelybenign(eg,steatosisand/ormild
elevationsofaminotransferases).

ScreeningAnnualscreeningforCFLDisrecommendedforallindividualswithCF[3,17]:

PhysicalexaminationExaminethepatientforhepatomegalyandsplenomegaly,notingcontour,
liverspan,andtexturebybothpalpationandpercussion.Itisimportanttonotethathepatomegaly
maybeasymmetric(duetoregenerativenodules),producingsubxiphoidhepatomegaly.

LaboratorytestingMeasureplateletcount,aspartateaminotransferase(AST),alanine
aminotransferase(ALT),andgammaglutamyltranspeptidase(GGTP),andalkalinephosphatase
atleastannually.AbnormalitiesinAST,ALT,andGGTParecommoninCFandhavelow
specificityandsensitivityforCFLD.Iftheresultsareabnormalbutthepatienthasno
hepatosplenomegalyorothersymptoms,itisreasonabletoobserveandrepeatthescreensix
monthslater.InCFLD,GGTPoralkalinephosphataseareoftenelevatedoutofproportiontoAST
andALT[29].Alargedropinplateletcountrelativetobaselineshouldbevigilantlyfollowedup,
evenifdoesnotmeetlaboratorycriteriaforthrombocytopenia,becausethisfindingmayindicate
progressiontosplenicsequestration.Lowalbumin,particularlyifpairedwithcoagulopathy,isa
signofsyntheticcompromiseandcansignaldecompensatedcirrhosis.(See'Furtherevaluation'
below.)

Iftheabovemeasuresarepersistentlyabnormal,thenthenextstepiscompleteabdominal
ultrasonography,withDopplermeasurementsofhepaticbloodflow.Ultrasonographycandetectearly
stagesofCFLD,whichincludecoarsenessofliverparenchyma,nodularityoftheliveredge,and
increasedperiportalechogenicity,andcanexcludegallstonesasacauseofintermittentlyelevated
GGTP.Whetherornotultrasound(eitherbyitselforcombinedwithotherclinicalparameters)can
predictprogressiontocirrhosisinpatientswithCFisbeingexploredinamulticenterstudyina
collaborationwiththeCFFoundation(CFF)andtheNationalInstitutesofHealth(NIH)(NCT01144507).
Dopplercanmeasurereversalofbloodflowintheportalveinorarecanalizedumbilicalvein,which
maybeseeninbothcirrhoticandnoncirrhoticportalhypertension.Clinicalevidenceofmoreadvanced
diseaseincludessplenomegaly,largecollateralveins,orascites[3,17,30].Althoughuncommon,
patientswithrightheartfailureduetopulmonarydisease(corpulmonale)mayhaveadditional
sonographicfindingsofhepaticcongestionanddilatedhepaticveins.Asgrayscaleultrasoundhas
difficultydifferentiatingfatfromfibrosis,magneticresonanceimaging(MRI)maybehelpfulforfurther
evaluationandconfirmationofdiseasewhenthereisclinicalsuspicionofsignificantCFLD[31].
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DiagnosisAdiagnosisofprogressiveCFLDismadeiftwoormoreofthefollowingfindingsare
present,assuggestedbybothaEuropeanpanel[3]andthejointNIH/CFFCFLDClinicalResearch
Workshop[32]:

Hepatomegaly(eg,liveredgepalpablemorethan2cmbelowthecostalmargin)and/or
splenomegaly,confirmedbyultrasonography.

AbnormalitiesofALT,AST,andGGTPabovethelaboratoryupperlimitsofnormalfor>6months,
afterexcludingothercausesofliverdisease.

Ultrasonographicevidenceofcoarseness,nodularity,increasedechogenicityorportal
hypertension,asdescribedabove.

Liverbiopsyshowingfocalbiliarycirrhosisormultilobularcirrhosis(ifperformed).

FurtherevaluationPatientssuspectedofhavingprogressiveCFLDbasedupontheclinical
featuresdescribedaboveshouldundergofurtherevaluationbyahepatologisttoassessforseverity
andexcludeothercausesofliverdisease.Theintensityoftheevaluationshouldbeguidedbythe
clinicalpresentation.Inpatientswithpersistentaminotransferaseelevations,theevaluationshould
includeacarefulhistory,askingspecificallyabouttheneonatalcourse,historyofjaundice,changein
activitylevel,changeinstoolpattern,abdominalpainornausea,weightloss,medicationintake
includingoverthecountermedicationsandsupplements,historyofbloodtransfusions,andfamily
historyofliverdisease.Thephysicalexaminationincludescarefulevaluationforhepatosplenomegaly,
andformanifestationsofchronicliverdiseasesuchasjaundice,spiderangiomata,palmarerythema,
andascites,althoughtheseareuncommoninCFLD.Signsorsymptomsofnutritionaldeficiencies
shouldalsobenoted.

AdditionallaboratoryevaluationforCFLDmayincludemarkersofliversyntheticfunctionsuchas
albuminandprothrombintimewithinternationalnormalizedratio(INR).Acompletebloodcount,
specificallyplateletcount,isusefultoscreenforhypersplenism,whichisassociatedwithportal
hypertension.Othercausesofliverdiseaseshouldberuledout,includinginfectioushepatitis(eg,
hepatitisC),Wilsondisease,alpha1antitrypsindeficiency,hemochromatosis,drugtoxicity,and
autoimmunedisease.Appropriatelaboratorytestsshouldbeperformedwhenindicated.(See
"Approachtothepatientwithabnormalliverbiochemicalandfunctiontests".)

Liverbiopsyisnotroutinelyneededtoassesstheseverityoftheliverdiseasebecausethefindings
rarelyaffectdecisionsaboutclinicalinterventions,suchasendoscopicvaricealbanding/sclerosisor
livertransplantation.Moreover,liverbiopsymayunderestimatetheseverityofdiseasebecausethe
lesionsofCFLDtendtobepatchyorheterogeneous[3].However,aliverbiopsymaybehelpfulfor
patientsinwhomthediagnosisofCFLDisunclear,particularlythosesuspectedofhavinga
concomitantliverdisease(ie,hepatitisC,drugtoxicity,orautoimmunehepatitis).

MANAGEMENT

NutritionForallpatientswithestablishedCFrelatedliverdisease(CFLD)(see'Diagnosis'above),
itisimportanttooptimizenutrition,includingensuringahighenergyintake,typicallytargeting150
percentoftherecommendeddailyallowance[3].MalabsorptionoffatsiscommoninCFLDbecauseof
insufficientorabnormalbileacidsintheintestinallumen,inadditiontotheunderlyingpancreatic
insufficiency.BecausepatientswithCFmayhaveinsulindeficiency(withorwithoutovertCFrelated
diabetes),supplementalenergyshouldbesuppliedprimarilybyfatsratherthancarbohydrates.The
fatsolublevitaminsshouldbemonitoredandvigorouslysupplemented(evenatmassivedoses)as
needed[3].PatientswithCFLDoftenrequirehigherdosesoffatsolublevitaminsupplements
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comparedwithotherpatientswithCF.(See"Cysticfibrosis:Nutritionalissues",sectionon'Fatsoluble
vitamins'.)

RiskreductionFullimmunizationagainsthepatitisAandhepatitisBisrecommendedforall
children,butisespeciallyimportantforindividualswithCFLD.Forthosewithprogressiveliverdisease,
wealsosuggest:

Avoidalcoholandprescribeddrugswithhepatotoxicsideeffects,includingcertainherbal
remedies.(See"Druginducedliverinjury".)

Avoidusingnonsteroidalantiinflammatorydrugs(NSAIDs)andsalicylicacid,tominimizerisksof
bleedingfromportalhypertensivegastropathy,orfromgastricoresophagealvarices,ifpresent
[3].

AzithromyciniscommonlyusedfortreatmentofpulmonarydiseaseinCF.Hepatotoxiceffectshave
occasionallybeenreported.Inmostcases,theestablishedbenefitsofazithromycinonpulmonary
diseaseprobablyoutweighthemodestrisktotheliver,unlessthereisclinicalevidencesuggestingthat
azithromycinisadverselyaffectingtheliverdiseaseinanindividualpatient.

UrsodeoxycholicacidTheroleofursodeoxycholicacid(UDCA)inCFLDhasnotbeenestablished
andiscontroversial.LimitedclinicalevidencesuggeststhatUDCAatmoderatedosesmayimprove
biochemicalparametersinpatientswithCFLD.However,thereisnogoodevidencethatitimproves
otheroutcomes,andindirectevidencefromothercholestaticliverdiseasessuggestthathighdoses
maybedetrimental.Inviewoftheseuncertainties,expertopiniondiffersastowhetherUDCAshould
beusedforallpatientswithCFLD,oronlythosewithsignificantcholestasisandfibrosis[17,33].

OurpracticeistogiveUDCAtochildrenwhohaveestablishedcholestasis(eg,conjugatedbilirubin>1
mg/dL[17.1micromol/L]),particularlythoseonorrecentlyweanedofftotalparenteralnutrition(TPN).
Weuseadoseof10to20mg/kgbodyweightperdayintwodivideddosesandcontinuefortwo
monthsbeyondresolutionofhyperbilirubinemia.WedonotuseUDCAforchildrenwithsubclinicalor
milderformsofCFLD.However,moreliberaluseofUDCAhasbeenadvocatedinthepastbyan
expertpanel,includingitsuseforchildrenwithearlyormildCFLD(eg,persistentlyelevated
aminotransferases),andescalatingthedoseifthereisnoimprovementinaminotransferase
concentrationsafterthreemonthsoftreatment[3].

UDCAisanontoxicbileacid,naturallyoccurringinhumans,andisthoughttoreduceliverinjuryin
cholestaticliverdiseasebyreplacingcytotoxicbileacids.Italsomayincreasebicarbonatesecretion,
andmayhaveadirectcytoprotectiveandantiinflammatoryeffect[20,34].Despitethesetheoretical
benefits,theclinicalevidencesupportingtheuseofUDCAisweak,andconsistsoflowqualityor
indirectclinicalevidence[35],asoutlinedbelow:

SeveralobservationalstudiesandtwosmallrandomizedtrialssuggestthatUDCAmaydelaythe
progressionofCFLD[3638].Oneoftherandomizedtrialsincluded55childrenandadultswith
CFLD,andreportedthatthosetreatedwithUDCAforoneyearexperiencedimprovementsin
gammaglutamyltranspeptidase(GGTP)andinaglobalmeasureofCFseverity,ascompared
withplacebo[37].Aseparatetrialinchildrenwhopresentedwithmeconiumileus(MI)atbirth(and
whowerethereforeatincreasedriskfordevelopingCFLD)reportedthattreatmentwithUDCA
reducedthelikelihoodofdevelopingchronicliverdiseasebynineyearsofage[39].

ACochranereviewfoundinsufficientevidencetodeterminewhetherUDCAiseffectivefor
treatmentorpreventionofCFLD[35].Threestudieswereincludedinvolvingcloseto120subjects,
twothirdsofwhomhadCFLDbasedoncriteriasimilartothoseoutlinedabove(largeliver,
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persistentlyelevatedhepaticenzymelevels).TheparticipantsweretreatedwithUDCAdoses
rangingfrom10to20mg/kg/dayforupto12months.Therewasnosignificantdifferenceinweight
gain.Noimprovementinbiliaryexcretionwasfoundintheonetrialthatmeasuredthisoutcome.
Therewerenodataavailableforanalysisforlongtermoutcomes,suchasdeathorneedforliver
transplantation.

IndirectevidencesuggestspossibleadverseeffectsofUDCAinhighdoses.Inarandomizedtrial
inadultswithprimarysclerosingcholangitis(PSC),chronictreatmentwithhighdoseUDCA(20to
30mg/kgperday)waslinkedtoimprovementinliverbiochemistryabnormalities,butalsowas
associatedwithhigherratesofseriousadverseeventsanddidnotimprovesurvival[40].Thetrial
wasterminatedatyearsixduetofutility.ThelimitedroleforUDCAinthemanagementofPSCis
discussedinaseparatetopicreview.(See"Primarysclerosingcholangitisinadults:Management",
sectionon'Ursodeoxycholicacid'.)

Indirectevidencefromstudiesinadultswithprimarybiliarycholangitis(PBC)suggestspossible
benefitofUDCAonsomemeasuresofcholestasis.InacohortofadultpatientswithPBC,UDCA
seemedtohaveabeneficialeffectonbothliverbiochemistrymeasuresandonhistological
progression,butdidnotimproveallcausemortalityorneedforlivertransplantation[41].Similar
conclusionswerereachedinametaanalysisthatincluded16randomizedtrials[42].Individual
trialsandanothermetaanalysishavereachedmoreoptimisticconclusions[43].(See"Trialsof
ursodeoxycholicacidforthetreatmentofprimarybiliarycholangitis(primarybiliarycirrhosis)".)

GallstonesinCFarenotresponsivetotherapywithUDCA,mostlikelybecausetheirmaincomponent
isnotcholesterol[17,25,44].(See'Gallbladderdisease'below.)

Managementofspecificcomplications

PortalhypertensionInpatientswithclinicalorradiographicsignsofportalhypertension,we
suggestuppergastrointestinalendoscopytoevaluateforesophagealvaricesandriskfor
gastrointestinalbleeding[3].Whetherprimaryprophylaxis(beforefirstvaricealbleed)withendoscopic
bandligationisindicatediscontroversial[45].Endoscopicbandligationshouldbeperformedfor
patientswhohaveexperiencedpriorvaricealbleeding(secondaryprophylaxis),particularlythosewho
havevariceswithcharacteristicsthatsuggestahighriskforbleeding(eg,redwaleoroverlyingulcer),
althoughspecificdataarelackingintheCFpatientpopulation.Multiplecoursesofbandligationmaybe
neededafterafirstvaricealbleed,andtendtohavealowerriskofbleedingthansclerotherapy.
AlthoughesophagealvaricesinadultpatientswithoutCFareoftentreatedwithnonselectivebeta
adrenergicblockers,theseagentsaregenerallyavoidedinpatientswithCFbecauseoftheirpotential
tocausebronchoconstriction.Moreover,betaadrenergicblockersusuallyareavoidedinchildrenwith
portalhypertensionbecausechildrenrelyonreflextachycardiatocompensateforacutevariceal
bleeding.Inanacutevaricealbleed,octreotidemaybeusedtodecreasesplanchnicflow,thus
decreasingthetensionongastroesophagealvarices.(See"Methodstoachievehemostasisinpatients
withacutevaricealhemorrhage"and"Preventionofrecurrentvaricealhemorrhageinpatientswith
cirrhosis"and"Primaryandpreprimaryprophylaxisagainstvaricealhemorrhageinpatientswith
cirrhosis".)

Placementofatransjugularintrahepaticportosystemicshunt(TIPS)isanappropriateoptionfor
patientswithrecurrentvaricealbleedingforwhomendoscopicbandligationisnotpossibleornot
effective.UseofTIPShasbeeneffectiveforCFpatientswithportalhypertensionasabridgeuntilliver
transplantation[4648].Improvementinbodymassindex(BMI)andlungfunctionafterTIPShasbeen
welldocumented.TIPSandanyotherportosystemicshuntmaybecomplicatedbyencephalopathyor
thrombus,thoughtheuseofnewconduitmaterialmaydecreasetheincidenceofocclusion.(See
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"Preventionofrecurrentvaricealhemorrhageinpatientswithcirrhosis",sectionon'Transjugular
intrahepaticportosystemicshunts'.)

HepatopulmonarysyndromePatientswithCFLDandportalhypertensionalsomaydevelop
hepatopulmonarysyndrome.Thisiscausedbydilationofthepulmonarycapillarybed,leadingtoa
functionalrighttoleftshuntandhypoxemia.Oneclinicalfeatureofhepatopulmonarysyndromeis
"orthodeoxia,"whichreferstoadecreaseinoxygenationintheuprightascomparedwithrecumbent
position.Patientswithportalhypertensionshouldbeevaluatedfororthodeoxiabymeasuringoxygen
saturation(usingpulseoximetry)inthesupineanduprightpositions.Asignificantdecreaseinoxygen
saturation(5percentagepoints)whenmovingintotheuprightpositionsuggestshepatopulmonary
syndrome,andshouldbefurtherevaluated[3].CFpatientswithhepatopulmonarysyndromeshouldbe
consideredforlivertransplantationandareeligibleforhigherprioritybasedonthisdiagnosis.(See
'Livertransplantation'belowand"Hepatopulmonarysyndromeinadults:Prevalence,causes,clinical
manifestations,anddiagnosis".)

PortopulmonaryhypertensionPortopulmonaryhypertension(orportopulmonarysyndrome)
referstopulmonaryarterialhypertensionthatisassociatedwithportalhypertension,andisawell
recognizedcomplicationofchronicliverdiseaseincludingCFLD.Aprovisionaldiagnosiscanbemade
withechocardiography.CFpatientswithportopulmonaryhypertensionshouldbeconsideredforliver
transplantation.Theymayreceivepriorityonthetransplantwaitinglist,asdopatientswith
hepatopulmonarysyndrome.(See'Livertransplantation'belowand"Portopulmonaryhypertension".)

LiverfailurePatientswithliverfailureorendstageliverdiseaseshouldbeconsideredforliver
transplantation,thoughthisisrare.Patientsshouldbereferredpromptlyforatransplantevaluation
becausewaitingtimeforalivermayexceedoneyearandbecauselivertransplantationmaystabilize
lungfunction[3,17].Evidenceofprogressivehepaticdysfunctionincludeshypoalbuminemia(<3g/dL
andfalling),and/orincreasingcoagulopathythatisnotcorrectedbyadministrationofvitaminK.(See
'Livertransplantation'below.)

LivertransplantationTheoptimaltimingoflivertransplantationinCFLDisoftencomplicatedby
nutritionalproblemsandprogressivepulmonarydisease.Recommendedindicationsforliver
transplantationinpatientswithCFLDinclude[3]:

Intractablevaricealbleedingthatisnotadequatelycontrolledbyothermeans.

Ascitesandjaundice.

Progressivehepaticdysfunction(hypoalbuminemiaandcoagulopathy).

Hepatopulmonarysyndrome.

Portopulmonaryhypertension.Ifportopulmonaryhypertensionispresent,eligibilityfor
transplantationmustbeevaluatedonacasebycasebasisbecausehighpulmonaryvascular
resistancemaybearelativeorabsolutecontraindicationtolivertransplantation.Medical
pharmacotherapyshouldbemaximizedfirst.

Deterioratingpulmonaryfunction,ifthisisthoughttobeaconsequenceoftheliverdisease
(hepatopulmonarysyndrome),becausethismayimproveafterlivertransplantation.Similarly,a
patientwithworseninghemoptysisthatisattributabletoportalhypertension(dueto
thrombocytopeniaorcoagulopathy)maybenefitfromlivertransplantation.

Severemalnutrition,unresponsivetointensivenutritionalsupportandtreatmentforcysticfibrosis

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relateddiabetes,ifpresent.

CFpatientsinwhombothlungandliverdiseaseareadvancedarecandidatesforliverlung
transplantation,butthecombinedprocedureisuncommon,particularlyinthepediatricagegroup
[16,4951].IntheUnitedStatesbetween1987and2009,combinedliverlungtransplantationwas
performedin8of210(4percent)oflivertransplantsforCFLDinchildrenandadolescents[16].Among
adults,combinedliverlungtransplantwasperformedin21of84(25percent)oflivertransplantsfor
CFLD.Thefrequencyofcombinedliverlungtransplantationvariesamonginstitutions.Asanexample,
atTexasChildren'sHospital,twooftheninechildrenwithCFLDwhoreceivedorthotopiclivertransplant
between1998and2008alsohadalungorlunghearttransplant,withoutgraftmorbidityorpatient
mortality[52].Between2008and2015,twoadditionalliverlungtransplantsandoneisolatedliver
transplantforCFLDwereperformedatthesameinstitution.(See"Cysticfibrosis:Overviewofthe
treatmentoflungdisease",sectionon'Lungtransplantation'.)

OveralloutcomesofpatientswithCFafterlivertransplantaresimilartothosewithotherformsofliver
disease,withaoneyearsurvivalofapproximately85percentandafiveyearsurvivalof64to78
percent[6,17,20,53](see"Livertransplantationinadults:Patientselectionandpretransplantation
evaluation").TheUnitedNetworkforOrganSharing(UNOS)reviewedoutcomesoftransplantation
proceduresforchildrenandadultswithCFbetween1987and2008,andreportedthatoneandfive
yearsurvivalweresimilarforpatientsundergoingonlylivertransplant,ascomparedwiththose
undergoingliverlungtransplant[51].Thus,eitherisolatedlivertransplantorliverlungtransplantare
viableoptionsforCFpatientswithendstageliverdisease.

GALLBLADDERDISEASECFisassociatedwithmicrogallbladder,cholelithiasis(gallstones),and
cholecystitis[6,17].

Microgallbladderisdefinedasagallbladdermeasuring<35mminthelongestaxisinadults,and
occursin25to30percentofpatientswithCF[3,54].Thepathogenesisisunclear.Onetheoryis
thatitiscausedbyadevelopmentalabnormalityofthefetalgallbladder,whichhashighexpression
ofCFtransmembraneconductanceregulatorgene(CFTR)[17].

Cholelithiasishasbeenreportedinupto12percentofpatientsandmayresultfromexcessiveloss
ofbileacidsinthestoolwithconsequentproductionoflithogenicbile[20,21].Asymptomatic
cholelithiasisgenerallydoesnotrequiretreatment,althoughprophylacticcholecystectomymaybe
performedinsuchpatientspriortolungtransplantationinsomecenters.Evaluationmayinclude
ultrasonographyormagneticresonancecholangiopancreatography(MRCP).Recurrentorsevere
biliarycolicmaywarrantcholecystectomy.(See"Choledocholithiasis:Clinicalmanifestations,
diagnosis,andmanagement".)

Cholecystitisistriggeredbybiliaryobstructionduetosludgeorgallstones.Evaluationand
managementissimilartothatforpatientswithoutCF.(See"Acutecholecystitis:Pathogenesis,
clinicalfeatures,anddiagnosis".)

SOCIETYGUIDELINELINKSLinkstosocietyandgovernmentsponsoredguidelinesfromselected
countriesandregionsaroundtheworldareprovidedseparately.(See"Societyguidelinelinks:Cystic
fibrosis".)

SUMMARYANDRECOMMENDATIONS

Therearemultiplepresentationsofcysticfibrosisrelatedliverdisease(CFLD)includingneonatal
cholestasis,hepaticsteatosis,andfocalbiliarycirrhosis(table1).Amongthese,focalbiliary
cirrhosisismostlikelytocauseprogressiveliverdisease,withassociatedcomplicationsand
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mortality.(See'Clinicalmanifestations'above.)

Cirrhosisdevelopsinabout10percentofindividualswithcysticfibrosis(CF).Thediseaseusually
developsduringchildhoodandinitsmostsevereformprogressesrapidlytoportalhypertension.
Mostsuchpatientsremaininastateofcompensatedcirrhosisforyearsordecades.Eventually,
someprogresstodecompensatedcirrhosis,heraldedbyascites,liverfailurewithsynthetic
dysfunction(coagulopathyandhypoalbuminemia)orhepaticencephalopathy.(See'Progressive
CFLD'above.)

AllpatientswithCFshouldbeevaluatedannuallyforCFLDbyexaminingforhepatosplenomegaly,
andlaboratorytesting,includingplateletcount,aspartateaminotransferase(AST),alanine
aminotransferase(ALT),andgammaglutamyltranspeptidase(GGTP),followedbyabdominal
ultrasonography,ifneeded.Thisscreeningprocessisparticularlyimportantforpatientswitha
severeCFgenotype(eg,homozygousfortheF508delmutation).(See'Evaluation'above.)

PatientswithCFLDrequirerigorousnutritionalmanagementwithclosemonitoringand
supplementationofenergyandfatsolublevitamins.Theyshouldavoidnonsteroidal
antiinflammatorymedications(NSAIDs)tominimizerisksofgastrointestinalbleeding,andtake
measurestominimizeinfectiousandtoxicinsultstotheliver.(See'Nutrition'aboveand'Risk
reduction'above.)

Theroleofursodeoxycholicacid(UDCA)inCFLDhasnotbeenestablished,particularlyregarding
whetherithasaroleinthetreatmentofsubclinicalorotherearlyformsofCFLD.Limitedclinical
evidencesuggeststhatUDCAatmoderatedosesmayimprovebiochemicalparametersinpatients
withCFLD.However,thereisnogoodevidencethatitimprovesotheroutcomes,andindirect
evidencefromothercholestaticliverdiseasessuggestthathighdosesmaybedetrimental.

WesuggestusingUDCAforchildrenwhohaveestablishedcholestasisduetoCFLD(Grade2C)
(eg,serumconjugatedbilirubin>1mg/dL[17.1micromol/L]),treatingwithdosesof20mg/kg/day.
ManycliniciansdonotuseUDCAforchildrenwithsubclinicalormilderformsofCFLD,butpractice
variesforthisgroupofpatientsthereisnospecificevidencethatitisharmfulinCF.(See
'Ursodeoxycholicacid'above.)

Patientswhodevelopportalhypertensionareatriskforhemorrhagefromesophagealvarices,
hepatopulmonarysyndrome,andportopulmonaryhypertensionthesecomplicationsmaybe
indicationsforlivertransplantation.Livertransplantationalsomaybeindicatedforpatientswith
progressivehepaticdysfunction,whichissuggestedbyfallingalbuminandcoagulopathy.(See
'Managementofspecificcomplications'aboveand'Livertransplantation'above.)

GallbladderdiseaseassociatedwithCFincludemicrogallbladder,cholelithiasis(gallstones)and
cholecystitis.EvaluationandmanagementissimilartothatforpatientswithoutCF.(See
'Gallbladderdisease'above.)

ACKNOWLEDGMENTTheauthorsandeditorialstaffaregratefultoDeborahSchady,MD,for
providingthehistologicimagesforthistopicreview.

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

REFERENCES

1.BartlettJR,FriedmanKJ,LingSC,etal.Geneticmodifiersofliverdiseaseincysticfibrosis.
https://www.uptodate.com/contents/cysticfibrosishepatobiliarydisease/print?source=search_result&search=liver%20cirrhosis&selectedTitle=10~150 10/19
3/5/2017 Cysticfibrosis:HepatobiliarydiseaseUpToDate

JAMA2009302:1076.
2.GelfondD,BorowitzD.Gastrointestinalcomplicationsofcysticfibrosis.ClinGastroenterolHepatol
201311:333.
3.DebrayD,KellyD,HouwenR,etal.Bestpracticeguidanceforthediagnosisandmanagementof
cysticfibrosisassociatedliverdisease.JCystFibros201110Suppl2:S29.
4.ColomboC,BattezzatiPM,CrosignaniA,etal.Liverdiseaseincysticfibrosis:Aprospective
studyonincidence,riskfactors,andoutcome.Hepatology200236:1374.
5.LamireauT,MonnereauS,MartinS,etal.Epidemiologyofliverdiseaseincysticfibrosis:a
longitudinalstudy.JHepatol200441:920.
6.WilliamsSG,WestabyD,TannerMS,MowatAP.Liverandbiliaryproblemsincysticfibrosis.Br
MedBull199248:877.
7.OppenheimerEH,EsterlyJR.Hepaticchangesinyounginfantswithcysticfibrosis:possible
relationtofocalbiliarycirrhosis.JPediatr197586:683.
8.VawterGF,ShwachmanH.Cysticfibrosisinadults:anautopsystudy.PatholAnnu197914Pt
2:357.
9.CysticFibrosisFoundationPatientRegistry,Annualdatareport,2012.Availableat:
http://www.cff.org/UploadedFiles/research/ClinicalResearch/PatientRegistryReport/2012CFF
PatientRegistry.pdf(AccessedonNovember05,2014).
10.LeeuwenL,MagoffinAK,FitzgeraldDA,etal.Cholestasisandmeconiumileusininfantswith
cysticfibrosisandtheirclinicaloutcomes.ArchDisChild201499:443.
11.CorbettK,KelleherS,RowlandM,etal.Cysticfibrosisassociatedliverdisease:apopulation
basedstudy.JPediatr2004145:327.
12.WilschanskiM,RivlinJ,CohenS,etal.Clinicalandgeneticriskfactorsforcysticfibrosisrelated
liverdisease.Pediatrics1999103:52.
13.RowlandM,GallagherCG,O'LaoideR,etal.Outcomeincysticfibrosisliverdisease.AmJ
Gastroenterol2011106:104.
14.ChamnanP,ShineBS,HaworthCS,etal.Diabetesasadeterminantofmortalityincystic
fibrosis.DiabetesCare201033:311.
15.MelziML,KellyDA,ColomboC,etal.Livertransplantincysticfibrosis:apollamongEuropean
centers.AstudyfromtheEuropeanLiverTransplantRegistry.TransplInt200619:726.
16.DesaiCS,GruessnerA,HabibS,etal.Survivalofcysticfibrosispatientsundergoingliverand
liverlungtransplantations.TransplantProc201345:290.
17.SokolRJ,DuriePR.Recommendationsformanagementofliverandbiliarytractdiseaseincystic
fibrosis.CysticFibrosisFoundationHepatobiliaryDiseaseConsensusGroup.JPediatr
GastroenterolNutr199928Suppl1:S1.
18.McKoneEF,EmersonSS,EdwardsKL,AitkenML.Effectofgenotypeonphenotypeand
mortalityincysticfibrosis:aretrospectivecohortstudy.Lancet2003361:1671.
19.AldmizEchevarraL,PrietoJA,AndradeF,etal.Persistenceofessentialfattyaciddeficiencyin
cysticfibrosisdespitenutritionaltherapy.PediatrRes200966:585.
20.ColomboC,BattezzatiPM.Hepatobiliarymanifestationsofcysticfibrosis.EurJGastroenterol
Hepatol19968:748.
21.BassS,ConnonJJ,HoCS.Biliarytreeincysticfibrosis.Biliarytractabnormalitiesincystic
fibrosisdemonstratedbyendoscopicretrogradecholangiography.Gastroenterology1983
https://www.uptodate.com/contents/cysticfibrosishepatobiliarydisease/print?source=search_result&search=liver%20cirrhosis&selectedTitle=10~150 11/19
3/5/2017 Cysticfibrosis:HepatobiliarydiseaseUpToDate

84:1592.
22.GreenholzSK,KrishnadasanB,MarrC,CannonR.Biliaryobstructionininfantswithcystic
fibrosisrequiringKasaiportoenterostomy.JPediatrSurg199732:175.
23.LykavierisP,BernardO,HadchouelM.Neonatalcholestasisasthepresentingfeatureincystic
fibrosis.ArchDisChild199675:67.
24.ShapiraR,HadzicN,FrancavillaR,etal.Retrospectivereviewofcysticfibrosispresentingas
infantileliverdisease.ArchDisChild199981:125.
25.AkataD,AkhanO,OzcelikU,etal.Hepatobiliarymanifestationsofcysticfibrosisinchildren:
correlationofCTandUSfindings.EurJRadiol200241:26.
26.PatriquinH,LenaertsC,SmithL,etal.Liverdiseaseinchildrenwithcysticfibrosis:US
biochemicalcomparisonin195patients.Radiology1999211:229.
27.TreemWR,StanleyCA.Massivehepatomegaly,steatosis,andsecondaryplasmacarnitine
deficiencyinaninfantwithcysticfibrosis.Pediatrics198983:993.
28.HultcrantzR,MengarelliS,StrandvikB.Morphologicalfindingsintheliverofchildrenwithcystic
fibrosis:alightandelectronmicroscopicalstudy.Hepatology19866:881.
29.BodewesFA,vanderDoefHP,HouwenRH,VerkadeHJ.IncreaseofSerum
GlutamyltransferaseAssociatedWithDevelopmentofCirrhoticCysticFibrosisLiverDisease.J
PediatrGastroenterolNutr201561:113.
30.WilliamsSG,EvansonJE,BarrettN,etal.Anultrasoundscoringsystemforthediagnosisofliver
diseaseincysticfibrosis.JHepatol199522:513.
31.ReederSB,CruiteI,HamiltonG,SirlinCB.Quantitativeassessmentofliverfatwithmagnetic
resonanceimagingandspectroscopy.JMagnResonImaging201134:729.
32.NationalInstitutesofHealth/CysticFibrosisFoundationClinicalResearchWorkshop,2009.
Availableat:
http://rarediseases.info.nih.gov/files/cystic%20fibrosis%20%28abstract%20book%29%20client%2
0review.pdf(AccessedonFebruary24,2015).
33.ColomboC.Liverdiseaseincysticfibrosis.CurrOpinPulmMed200713:529.
34.PouponR.Ursodeoxycholicacidandbileacidmimeticsastherapeuticagentsforcholestaticliver
diseases:anoverviewoftheirmechanismsofaction.ClinResHepatolGastroenterol201236
Suppl1:S3.
35.ChengK,AshbyD,SmythRL.Ursodeoxycholicacidforcysticfibrosisrelatedliverdisease.
CochraneDatabaseSystRev2014:CD000222.
36.NousiaArvanitakisS,FotoulakiM,EconomouH,etal.Longtermprospectivestudyoftheeffect
ofursodeoxycholicacidoncysticfibrosisrelatedliverdisease.JClinGastroenterol200132:324.
37.ColomboC,BattezzatiPM,PoddaM,etal.Ursodeoxycholicacidforliverdiseaseassociatedwith
cysticfibrosis:adoubleblindmulticentertrial.TheItalianGroupfortheStudyofUrsodeoxycholic
AcidinCysticFibrosis.Hepatology199623:1484.
38.KapplerM,EspachC,SchweigerKabeschA,etal.Ursodeoxycholicacidtherapyincysticfibrosis
liverdiseasearetrospectivelongtermfollowupcasecontrolstudy.AlimentPharmacolTher
201236:266.
39.SianoM,DeGregorioF,BoggiaB,etal.Ursodeoxycholicacidtreatmentinpatientswithcystic
fibrosisatriskforliverdisease.DigLiverDis201042:428.
40.LindorKD,KowdleyKV,LuketicVA,etal.Highdoseursodeoxycholicacidforthetreatmentof
https://www.uptodate.com/contents/cysticfibrosishepatobiliarydisease/print?source=search_result&search=liver%20cirrhosis&selectedTitle=10~150 12/19
3/5/2017 Cysticfibrosis:HepatobiliarydiseaseUpToDate

primarysclerosingcholangitis.Hepatology200950:808.
41.PapastergiouV,TsochatzisEA,RodriguezPeralvarezM,etal.Biochemicalcriteriaat1yearare
notrobustindicatorsofresponsetoursodeoxycholicacidinearlyprimarybiliarycirrhosis:results
froma29yearcohortstudy.AlimentPharmacolTher201338:1354.
42.RudicJS,PoropatG,KrsticMN,etal.Ursodeoxycholicacidforprimarybiliarycirrhosis.
CochraneDatabaseSystRev201212:CD000551.
43.ShiJ,WuC,LinY,etal.Longtermeffectsofmiddoseursodeoxycholicacidinprimarybiliary
cirrhosis:ametaanalysisofrandomizedcontrolledtrials.AmJGastroenterol2006101:1529.
44.GuarinoMP,CoccaS,AltomareA,etal.Ursodeoxycholicacidtherapyingallbladderdisease,a
storynotyetcompleted.WorldJGastroenterol201319:5029.
45.ShneiderBL,BoschJ,deFranchisR,etal.Portalhypertensioninchildren:expertpediatric
opiniononthereportoftheBavenovConsensusWorkshoponMethodologyofDiagnosisand
TherapyinPortalHypertension.PediatrTransplant201216:426.
46.BloomAI,VerstandigA.SCVIR2002FilmPanelcase2:TIPSforbleedingvaricesincystic
fibrosisandlivercirrhosis.JVascIntervRadiol200213:533.
47.PozlerO,KrajinaA,VanicekH,etal.Transjugularintrahepaticportosystemicshuntinfive
childrenwithcysticfibrosis:longtermresults.Hepatogastroenterology200350:1111.
48.RobberechtE,VanBiervlietS,VanrentergemK,KerremansI.Outcomeoftotalsplenectomywith
portosystemicshuntformassivesplenomegalyandvaricealbleedingincysticfibrosis.JPediatr
Surg200641:1561.
49.FaroA,ShepherdR,HuddlestonCB,etal.Lowerincidenceofbronchiolitisobliteransinpediatric
liverlungtransplantrecipientswithcysticfibrosis.Transplantation200783:1435.
50.YiSG,BurroughsSG,LoebeM,etal.Combinedlungandlivertransplantation:analysisofa
singlecenterexperience.LiverTranspl201420:46.
51.ArnonR,AnnunziatoRA,MilohT,etal.Liverandcombinedlungandlivertransplantationfor
cysticfibrosis:analysisoftheUNOSdatabase.PediatrTransplant201115:254.
52.HarringTR,NguyenNT,LiuH,etal.Livertransplantationincysticfibrosis:areportfromBaylor
CollegeofMedicineandtheTexasChildren'sHospital.PediatrTransplant201317:271.
53.FridellJA,BondGJ,MazariegosGV,etal.Livertransplantationinchildrenwithcysticfibrosis:a
longtermlongitudinalreviewofasinglecenter'sexperience.JPediatrSurg200338:1152.
54.DietrichCF,ChichakliM,HircheTO,etal.Sonographicfindingsofthehepatobiliarypancreatic
systeminadultpatientswithcysticfibrosis.JUltrasoundMed200221:409.

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GRAPHICS

Clinicalpresentationsofcysticfibrosisrelatedliverdisease

Approximate
frequencyin
Category Typicalcharacteristics
individuals
withCF

Neonatal <10% Conjugatedhyperbilirubinemiainaneonate,oftenwith

cholestasis hepatomegaly.Usuallyregresseswithinmonthsandisnota
predictoroflaterCFLD,unlessthereisprolongedTPN
exposureorsurgeryrelatedtoMI.

Focalbiliary 20to40% Mayormaynotbeassociatedwithpersistentlyelevated

cirrhosis aminotransferasesandhepatomegaly,usuallyasymptomatic
anddevelopingwithinthefirst12yearsoflife.

Multilobular 5to10% Advancedstageoffocalbiliarycirrhosis.Maybecomplicated

cirrhosis byportalhypertension(causingsplenomegaly,ascites,and
esophagealvarices),gastrointestinalbleeding,andnutritional
deficiencies.Hepaticsyntheticdysfunction(coagulopathyand
hypoalbuminemia)isalateandrareoccurrence.

Hepaticsteatosis 10to60% Incidentalfindingonultrasoundorliverbiopsy,withtransient

hepatomegaly.Therelationshipbetweenhepaticsteatosisand
thedevelopmentoffocalbiliarycirrhosisinCFisunclear.May
beseenfrominfancytoadolescence,andmaybeassociated
withstuntingorwasting.
Steatosismaybecausedbyiatrogenicorenvironmentalfactors
suchasmalnutrition,medications,essentialfattyacid
deficiency,andethanolingestion.

CF:cysticfibrosisCFLD:cysticfibrosisrelatedliverdiseaseTPN:totalparenteralnutritionMI:meconium
ileus.

References:
1.C olomboC,BattezzatiPM,CrosignaniA,etal.Liverdiseaseincysticfibrosis:Aprospectivestudyon
incidence,riskfactors,andoutcome.Hepatology200236:1374.
2.LamireauT,MonnereauS,MartinS,etal.Epidemiologyofliverdiseaseincysticfibrosis:alongitudinal
study.JHepatol200441:920.
3.DebrayD,KellyD,HouwenR,etal.Bestpracticeguidanceforthediagnosisandmanagementofcystic
fibrosisassociatedliverdisease.JCystFibros201110Suppl2:S29.

Graphic100004Version2.0

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Focalbiliarycirrhosisincysticfibrosis

Focalbiliaryfibrosiswithbileductularproliferation,eosinophilicconcretions,andbileplugs,withincreased
portalfibrosisadjacenttorelativelyunremarkablehepaticparenchyma.

CourtesyofDeborahSchady,MD,BaylorCollegeofMedicine.

Graphic99940Version2.0

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Multilobularcirrhosisincysticfibrosis

"Multilobularcirrhosis"withentrappedlobulesofhepaticparenchymasurroundedbybandsoffibrosis.

CourtesyofDeborahSchady,MD,BaylorCollegeofMedicine.

Graphic99941Version2.0

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Neonatalcholestasisincysticfibrosis

(A)Bileductularproliferationwithinspissatedhypereosinophilicconcretionsandacutecholangitis(magnification200x)
(B)Hypereosinophilicinspissatedmaterialwithinductsandductules,withfocalatrophyoftheductularepithelium,and
acutecholangitisandbileductuleproliferation(magnification400x).

CourtesyofDeborahSchady,MD,BaylorCollegeofMedicine.

Graphic99938Version2.0

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Hepaticsteatosisincysticfibrosis

Liverparenchymawithdiffusemacrovesicularsteatosiswithmicrovesicularsteatosis(magnification200x).

CourtesyofDeborahSchady,MD,BaylorCollegeofMedicine.

Graphic99939Version2.0

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ContributorDisclosures
DanielHLeung,MD Grant/Research/ClinicalTrialSupport:CFFoundation[DIGESTgrant]Bristol
MeyersSquibbGileadAbbvieRoche.Consultant/AdvisoryBoards:Vertex[CFnutritionandgrowth
(ivacaftor,lumacaftor)]. DrucyBorowitz,MD Nothingtodisclose GeorgeBMallory,MD Nothingto
disclose ElizabethBRand,MD Nothingtodisclose AlisonGHoppin,MD Nothingtodisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.

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