Liver

KasaiProcedure

Smallintestine attached directlytoliver

Stomach

Smallintestine

Smallintestine Restofintestinestitchedto smallintestinetoformthe Rouxen Y connection

Hepatoportoenterostomy, alsoknownastheKasaiprocedure, isasurgicalprocedureusedtotreatinfantsandchildrenwithbiliaryatresia, asevere formofliverdiseasemarkedbydestructionofbileducts, bileretention(cholestasis), andliverdamage. Inthisprocedure, thedamagedbileductsare removedandaportionofthesmallintestineisattachedtotheundersideofthelivertodrainthebiledirectlyintotheintestine, whereitaidsinfat digestion. Theupperintestineandstomachareconnectedtotherestoftheintestine. Ifperformedwithintherstfewmonthsoflife, thisprocedure maypartiallyrestorebileowandpreventliverfailure.

CHAPTER10:
PEDIATRICLIVERDISEASE

INTRODUCTIONANDBACKGROUND Pediatricliverdiseasesincludebiliaryatresia, meta bolicdisorders, intrahepaticcholestaticdisorders, alpha1antitrypsindeciencyliverdisease, nonalco holicsteatohepatitis(NASH), autoimmunehepatitis andsclerosingcholangitis, parenteralnutritionand druginducedliverinjury, Wilsondisease, cysticbro sis, andthevariousformsofviralhepatitis. While liverdiseaseisuncommoninchildhood, thoseliver diseasesthatoccurtendtobesevereandprogres sive. Manyoftheseconditionsareofunclearetiology, and, formost, therearenoeffectivemedicalthera pies. Livertransplantationisaneffectivemeansof reversingacuteliverfailureoradvancedendstage liverdiseaseinchildrenandeachyearapproximately 500livertransplantsaredoneintheUnitedStatesin thepediatricagegroups. Whilelivertransplantation isoftenhighlysuccessful, thechildthenfacesalife ofmanagingtheproblemsofimmunosuppression andlivingwiththetransplantedorgan. Ofcourse, manyoftheliverdiseasesthataffect Themostcommon, severeliverdiseaseofchildren isbiliaryatresiawhichaffectsapproximately510per 100,000newborns. Biliaryatresiaischaracterizedby a progressiveinammatoryandbrousobliteration ofthelargeandintermediateintraandextrahepatic bileducts. Thisprocessleadstocholestasis, progres siveliverbrosis, andcirrhosis. Withoutintervention, childrendieofendstageliverdiseasewithintherst fewyearsoflife. TheKasaiprocedure(hepatopor toenterostomy), ifdonewithintherstfewmonths oflife, canpartiallyrestorebileowandpreventliver failure. Nevertheless, morethantwothirdsofchildren adultscanoccurorhavetheironsetinchildhood. ProminentamongthesearehepatitisBandC, NASH, Wilsondisease, autoimmunehepatitis, andsclerosing cholangitis. Importantly, advancesmadeinthepre ventionandtreatmentoftheseadultliverdiseases havenotalwaysbeenappliedtoorassessedade quatelyinchildren. Differencesindiseasepresenta tion, complications, andprogressionmakeitdifficult toextrapolateresultsoftherapyinadultstochildren. Inparticular, theimplicationsofstartinglongterm, possiblylifelong, therapyforachronicliverdisease arequitedifferentforchildrenthanforadults. Otherseriouschildhoodliverdiseasesincludeneona talhepatitis, threeformsofprogressivefamilialintra hepaticcholestasis(PFIC1, 2, and3), Alagillesyn drome, alpha1antitrypsindeciency, mitochondrial hepatopathies, andseveralotherinheritedmetabolic abnormalities. Thegeneticbasesforsomeofthese conditionsareknown, butmanyremainelusive, and therearenoeffectivetherapiesformost, shortof livertransplantation. withbiliaryatresiawilleventuallyrequiretransplanta tion, andthisdiagnosisisthesinglemostcommon reasonforlivertransplantationinchildren. Thecause ofbiliaryatresiaisunknown; itpresentssoonafter birth, butdoesnotappeartobeinherited. Hypotheses regardingtheetiologyofbiliaryatresiaimplicate peri natalinfections, immuneabnormalities, andsomatic mutationsinlateralitygenes.

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RECENTRESEARCHADVANCES Importantadvanceshavebeenmaderecentlyin theunderstandingofliverdiseaseinchildren. Pathogenesis: Moststrikingly, manyofthegenesof theinheritedformsofliverdiseaseinchildrenhave beenidentied, andtheelucidationoftheresulting biochemicalandmoleculardefectspromisestopro videmeansofpreventionandtreatmentofthese diseases. Thus, thegeneforWilsondiseasehasbeen showntocodeforacoppertransportingATPasethat isrequiredfornormalcopperexcretionbytheliver. ThegeneforAlagillesyndromehasbeenshownto codeforJagged1, whichisaligandintheNotch signalingpathwaythatisimportantincelldifferentia tion. Thegenesandtheproteinproductsofsome formsofPFIChavebeenidentied(FIC1, BSEP, andMDR3), allofwhichappeartoparticipatein bilesecretion. Thebiochemicalbasisofhereditary tyrosinemiahasbeenelucidated, andaninhibitorof tyrosinemetabolismwasfoundtoreversethemeta bolicabnormalityandrescueinfantswithliverfailure resultingfromthisdisease. PreventionandTherapy: Vaccinesagainsthepatitis A andBhavehadmajoreffectsontheincidenceof acuteandchronichepatitisinchildren. Theuseof universalhepatitisBvirusvaccinationhasalready decreasedthefrequencyofchronichepatitisB andlivercancerinthepediatricpopulationinChina. Introductionofroutinescreeningofbloodforhepati tisBandChaseliminatedposttransfusionand bloodproductassociatedhepatitis, whichwere previouslyimportantcausesofhepatitisinchildren. Nevertheless, pediatriccasesofchronichepatitisB andCarestillseen, mostasaresultofmaternal infanttransmissionand/oremigrationfromareas oftheworldwherethesediseasesarecommon. TherapyofhepatitisBandChasadvancedsubstan tiallyinthelast10to15years. However, thesethera pieshavebeenappliedtoonlysmallnumbersof Approachestoelucidationofthecauseofbiliary atresiacouldincludecarefulanalysisofcohortsof patientswiththisdiseaseandapplicationofstateof theartmeansofassessinggenes, generegulation, proteins, lipids, environmentalfactors, andinfectious ResearchGoal: Todenetheetiologyofbiliary atresia(MatrixCellC3). PathogenesisandManagementofBiliaryAtresia: The underlyingcausesofseveralimportantliverdiseases inchildrenremainelusive. Mostimportantly, theetiol ogyofbiliaryatresiaisunknown, andthesearchfor thecauseisahighpriority. Themajorgoalsforresearchonpediatricliverdis easesaretoelucidatethecausesofthesediseases andtodeveloppracticalmeansoftheirdiagnosis, treatment, andprevention. RESEARCHGOALS Duetothelackofeffectivemedicaltherapies, liver transplantationhasbecomethestandardtreatment forendstageaswellasfulminantliverdiseasein children. Advancesinsurgicaltechniquesand immunosuppressiveregimenshaveimprovedshort andlongtermoutcomesforchildrenundergoing transplantation. Importantly, theuseofreducedliver grafts, splitlivers, andlivingdonorlivershasmaterial lyimprovedtheprognosisofchildrenwithadvanced liverdisease, decreasingthewaitinglistmortalityand providingbetteroptionsforchildrenfacingthedebili tyandburdenofendstageliverdisease. children, andtheoptimalregimen, ratesofresponse, predictivefactors, andshortandlongtermsafetyof thesetherapieshaveyettobedened.

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agents. Developmentofnetworksofinterdisciplinary groups(clinicians, molecularbiologists, geneticists, virologists)tostudybiliaryatresiawouldhelpto achievethisgoal. Theunderstandingofbiliaryatresiaandmanyother pediatricliverdiseaseswouldbeaidedbyabetter understandingofnormalorganogenesisoftheliver andbiliarysystemduringfetallifeandafullcharac terizationofthestructuralandfunctionalchanges thatoccurwithdevelopmentoftheliver. ResearchGoal: Tocharacterizethestructural andfunctionaldevelopmentoftheliverandbiliary system(MatrixCellB1; seealsoChapter3, C3). Finally, clinicaltrialsareimportanttoensureopti mizationofthemedicalandsurgicalmanagement ofbiliaryatresiawithafocusonmethodsofearly noninvasivediagnosisandwaystoimprovethe successoftheKasaioperation. MolecularPathogenesisandTreatmentofNeonatal CholestaticSyndromes: Despitetheidentication ofmanyofthegenesthatcauseneonatalcholestatic liverdisease, theseadvanceshavesofarfailedto resultinpracticalmeansofprevention, treatment, andcureofthesediseases. Furthermore, thecause ofmanycasesofneonatalcholestasiscannotbe identied. Thus, manycasesofPFIChavenomuta tionsinFIC1, BSEP, orMDR3, andtheirunderlying etiologyremainsunclear. Research Goal: To furtherinvestigatethemolecular pathogenesisoftheneonatalcholestaticsyn dromesinordertodenehowthegeneticdefects leadtoliverandbiliarycellinjury(MatrixCellB2; seealsoChapter4, A1). Research Goal: To developanimalmodelsforthese diseasesthatwouldhelpdenethemolecular mechanismsbywhichthesegenesaffectnormal liverandbiliaryfunction(MatrixCellB2).

Forgeneticdiseases, anapproachusingtransgenic micewiththeabnormalhumangenewouldprovide a meanstobetterelucidatethemechanismsof cellinjury. Animalmodelswouldalsobeimportant inprovidinginsightsintomodifyinggenesand environmentalinuencesinexpressionofdisease, aswellasinsightsintotherapeuticapproaches. Importantly, animalmodelswouldprovidethemeans toevaluatenewtherapies, whichisexceedingly difficultfortheserelativelyrareandseverediseases. Finally, animalmodelsmightallowforthedevelop mentofpracticalmeansofmoleculartherapyof theseinheriteddiseases, suchastheuseofsmall interferingRNA(siRNA), genetherapy, hepatocyte transplantation, orstemcellbasedcorrectionof metabolicabnormalities. Research Goals: To developnewapproachesto therapy, eitherusingdrugsorsmallmoleculesto helpcorrectorbypassthelossorblockoffunction (MatrixCellC2)orbyusingmolecularapproaches, genetherapy, orhepatocytecelltransfer(Matrix CellC3; seealsoChapters4and11, C3). Clinicalstudiesfocusingonthenaturalhistoryand managementofpatientswithcholestaticsyndromes areimportant. A majorcurrenthandicapisthelack ofnoninvasivemeansforaccuratediagnosis, staging, andgradingofdisease. ResearchGoals: Toapplytheevolvingtoolsof genetics, genomics, genearrays, proteomics, and metabolomicstowellcharacterizedpatientsin ordertodevelopnewhypothesesregardingpatho genesis, modifyingfactors, andgenesandtodevel opbiomarkersfordiagnosis, staging, andgrading ofdisease(MatrixCellsB2andB3). CharacterizationandTreatmentofPediatricLiver DiseasesBeyondtheNeonatalPeriod: Theburden ofliverdiseaseinchildrenintheUnitedStatesis notwelldened. Epidemiologicandclinicalstudies

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wouldbehelpedbystandardizationofnomenclature, denitions, anddiagnosticcriteriaforpediatric liverdiseases. ResearchGoal: Todevelopbettersystemsto characterizethefrequencyandepidemiologyof liverdiseasesinchildhoodandtohelpdelineate theirnaturalhistory(MatrixCellA2). ResearchGoal: Todenestandardizednomencla ture, denitions, diagnosticcriteria, andgradingand stagingsystemsforthemajorneonatalcholestatic syndromes(MatrixCellA1; seealso: Chapter8, A1; Chapter9, B2; Chapter14, B1; Chapter16, A1). Clinicaltrialsinchildrenofantiviralagentsforviral hepatitisthathavebeenfoundtobeeffectivein adultswouldhelptodenetheoptimalregimens oftherapy, responserates, predictorsofresponse, tolerability, andsafety. Amajorcomponentofthese studiesshouldbeassessingeffectsoftherapyon growth, development, andqualityoflife, aswellas ancillarystudiesfocusingongeneticmodiersof diseaseprogression, noninvasivemarkersofbrosis, andearlybiomarkersforhepatocarcinogenesis. Nonalcoholicsteatohepatitis(NASH)isanemerging liverdisease, whichisincreasingmarkedlyinfrequen cyasaresultoftherecentincreasesinobesityin theUnitedStates. Originallydescribedasadisease ofmiddleaged, overweightwomenwithdiabetes, NASHhasnowbeenshowntoaffectallagegroups includingyoungchildren. Research Goal: To identifyclinicalcohortsofchil drenwithNASHinordertocharacterizetheclinical syndrome, naturalhistory, course, andcomplica tionsofthisdiseaseinthepediatricagegroup (MatrixCellA1). Ideally, theseresearchstudieswouldengageboth basicandclinicalresearchersinattemptstodene theetiologyandpathogenesisofNASHandtoprovide

insightsintopossiblemeansoftherapy. Clinical trialsofnewagentsforNASHinadultsshouldbe matchedwithsimilartrialsinchildren, withas littledelayaspossible. OptimizationofLiverTransplantationinChildren: Livertransplantationishighlysuccessfulinchildren, butitstillpresentsmajorchallenges. Longterm outcomeandcomplicationsarepoorlycharacterized andrequirefollowupoflargecohortsofcarefully evaluatedtransplantrecipients. Mostlongterm complicationsoftransplantationareduetothe immunesuppressionthatisrequiredtoprevent rejection. Amajorchallengeinlivertransplantation ishowtominimizeimmunosuppressionwithout sacricinggraftfunction. Research Goal: To prospectivelystudythenature ofimmunetolerance, evaluatenewtolerance inducingregimens, delineatefactorsassociated withtolerance, anddevelopbiomarkersthat accuratelypredictthenecessaryamountof immunesuppression(MatrixCellB1; seealso Chapter12, C1andC2). Emphasisshouldalsobeplacedonidentifying waystoavoidtheneedforlivertransplantation. Forchildrenwithbiliaryatresia, livertransplantation maybeavoidedoratleastdelayedbyearlydiag nosis, successfulKasaioperation, andinstitution ofeffectiveanticholestaticandantibrotic therapiesthereafter. Research Goals: To identifybiomarkersforearly diagnosisanddevelopameanstooptimize theKasaiprocedure(MatrixCellsB3andC1). Effortstoreducetheneedforlivertransplantation arealsowarrantedforacuteliverfailureofunknown cause, whichisthesecondmostcommonreason forlivertransplantationinchildren.

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 ResearchGoals: To identifytheetiologyofcrypto genicacuteliverfailureinchildren(MatrixCellA3) andtodevelopbothspecicandnonspecicmeans ofitspreventionandamelioration(MatrixCellC1).

researchinotherinheritedcholestaticliversyn dromeswouldbehelpedbyexpandingtheBARC networktoincludeotherneonatalliverdiseases suchasAlagillesyndrome, PFIC, alpha1antitrypsin deciency, bileacidmetabolismdisorders, andthe mitochondrialhepatopathies. Understandingand managementoftheserarediseaseswouldbegreatly

STEPSTOACHIEVERESEARCHGOALS Useofexistingmechanisms, aswellasnewones, willhelptoachievethemajorresearchgoalsin pediatricliverdisease. Thus, epidemiologicalsystems thathavebeendevelopedprimarilyforadultliver diseaseshouldbeencouragedtoincludeacompo nentfocusingonpediatricliverdisease. Examples ofsuchsystemsaretheNHANESsurveyandthe CDCsurveillancesystemsforacuteandchronicliver disease. Similarly, NIHfundednetworksonliverdis easeinadults(suchasthoseinNASHorautoimmune liverdiseases)shouldincludepediatriccomponents, andstudiesoftherapyinadultswithchronichepatitis B andCshouldbematchedwithstudiesinchildren. ThenewlyfundedcohortStudyonPediatricLiver Transplantrecipients(SPLIT)couldserveasan instrumentforinvestigatinglongtermoutcomes, complications, andtoleranceinchildrenundergoing livertransplantation. Advancesinunderstandingofbiliaryatresiaarelikely toresultfromthenewlyformulatedBiliaryAtresia ResearchConsortium(BARC), whichisamulticenter studyfocusingupondevelopingcohortsofwell characterizedpatientsfollowedprospectively. An importantroleforBARCistodevelophypotheses regardingetiologyandtherapyofbiliaryatresiaand helptotestthesehypothesesinpatientmaterial. BARCcouldalsoserveasagrouptoprovidesamples fordevelopmentofbiomarkersforthenoninvasive diagnosisandstagingofdiseaseandtodevelop clinicaltrialsfocusingonoptimizingmanagementof biliaryatresia. Theadvantagesofaclinicalresearch networkinbiliaryatresiaaremany. Advancesin

enhancedbyfocusedattentionandinvestigation byamulticenternetworkofinvestigators. Suchan expandednetworkcouldprovideserumsamples, DNAmaterials, andliverandbiliarytissuestoinvesti gateetiologyandpathogenesis; establishreliable denitionsanddiagnosticcriteriaforthesediseases; andprovidenationalcentersofexcellenceforDNA baseddiagnosis. Thisnetworkmightalsoestablish resourcesandsourcesofsupportforpatients andtheirfamilies. Benetswouldowfromtheplacementofa continuedemphasisonbasicresearchontheliver ascomplementarytoresearchonspecicpediatric liverdiseases. Ofparticularimportancearestudies ofembryogenesis, organdevelopment, angiogenesis, biliarycelldifferentiation, andhepatocytefunction. Otherimportantareasarestemcellresearch andgenetherapy, includingthedevelopmentof betterandsafermethodsforhumangeneand celltransfer. Thedevelopmentofanimalmodels forbiliaryatresiaandtheneonatalcholestatic syndromesisofcriticalimportance. Mechanisms wouldalsobeusefulforsupportingthedevelopment ofnewanimalmodels, aswellasthescreening, identication, andpreclinicaltestingofsmall moleculesfortherapyandprevention.

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MatrixofResearchGoalsinPediatricLiverDisease

ShortTerm (03years) HighRisk A3. Elucidatethemajor causeofidiopathicacute liverfailureinchildren.

IntermediateTerm (46years) B3. Identifybiomarkers fordiagnosis, staging, andgradingofneonatal cholestaticsyndromes.

LongTerm (710years) C3. Denetheetiology ofbiliaryatresia. Developgene, siRNA, celltransfer, orstem celltherapyforpediatric metabolicdisease.

IntermediateRisk

A2. Developsystemsto bettercharacterizethe frequency, medicalburden, andepidemiologyof pediatricliverdisease.

B2. Delineatethemolecular pathogenesisofatleast3 oftheneonatalcholestatic syndromes. Developbetteranimal modelsforneonatal cholestaticsyndromes.

C2. Baseduponmolecular pathogenesis(B2), identify smallmoleculetherapies thatmightalleviateneonatal cholestaticsyndromes.

LowRisk

A1. Characterizeclinical syndrome, naturalhistory, etiology, cofactors, and complicationsofpediatric NASH. Developdenitionsand diagnosticcriteriaforthe majorneonatalcholestatic syndromes.

B1. Denestructuraland functionaldevelopmentof theliverandbiliarysystem. Evaluatelongterm outcomes, complications, and toleranceinducingregimens inchildrenundergoingliver transplantation.

C1. Conductclinicaltrials to optimizemedicaland surgicalmanagementof biliaryatresia. Evaluatetherapiesfor acuteliverfailureinchildren.

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ActionPlanforLiverDiseaseResearch