新生儿和婴儿胆汁淤积(英文版)课件.ppt

1、Neonatal and Infantile CholestasisYing-kit Leung,MD,FAAPPresident,Hong Kong Society of Paediatric Gastroenterology,Hepatology and Nutrition,Yantai,Shandong,July 2006DEFINITIONnNeonatal cholestasis is defined as conjugated hyperbilirubinemia developing within the first 90 days of extrauterine life.nC

2、onjugated bilirubin exceeds 1.5 to 2.0 mg/dl.nConjugated bilirubin generally exceeds 20%of the total bilirubin.Bilirubin ProductionBiliverdinBilirubinerythrocytehemoglobinmusclemyoglobincytochromescatalaseshemeoxygenasebiliverdinreductasereticulo-endothelial cellBilirubinAlbuminliverCO+FeHemeGSTBili

3、rubinUptake,Conjugation,ExcretionBBAlbGBGGBRUDPGUDPGLUCURONYLTRANSFERASEHEPATOCYTESINUSOIDDISSEBILECANALICULUS2.UPTAKE3.CONJUGATION4.EXCRETIONE.R.B-GB-GB-B-GB-GB-GBuBgsBuBgB-Gdark urineacholic stoolsConjugated HyperbilirubinemiaConjugatedhyperbilirubinemiaextrahepaticintrahepaticNeonatal Cholestasis

4、EXTRAHEPATIC ETIOLOGIESnExtrahepatic biliary atresianCholedochal cystnBile duct stenosisnSpontaneous perforation of the bile ductnCholelithiasisnInspissated bile/mucus plugnExtrinsic compression of the bile ductINTRAHEPATIC ETIOLOGIESnIdiopathicnToxicnGenetic/ChromosomalnInfectiousnMetabolicnMiscell

5、aneousINTRAHEPATIC ETIOLOGIESnIdiopathic Neonatal HepatitisnToxicnTPN-associated cholestasisnDrug-induced cholestasisINTRAHEPATIC ETIOLOGIESnInfectiousINTRAHEPATIC ETIOLOGIESnMetabolicnDisorders of Carbohydrate MetabolismnGalactosemianFructosemianGlycogen Storage Disease Type IVnDisorders of Amino A

6、cid MetabolismnTyrosinemianHypermethioninemiaINTRAHEPATIC ETIOLOGIESnMetabolic(cont.)nDisorders of Lipid MetabolismnNiemann-Pick diseasenWolman diseasenGaucher diseasenCholesterol ester storage diseasenDisorders of Bile Acid Metabolismn3B-hydroxysteroid dehydrogenase/isomerasenTrihydroxycoprostanic

7、acidemiaINTRAHEPATIC ETIOLOGIESnMetabolic(cont.)nPeroxisomal DisordersnZellweger syndromenAdrenoleukodystrophynEndocrine DisordersnHypothyroidismnIdiopathic hypopituitarismINTRAHEPATIC ETIOLOGIESnMetabolic(cont.)nMiscellaneous Metabolic DisordersnAlpha-1-antitrypsin deficiencynCystic fibrosisnNeonat

8、al iron storage diseasenNorth American Indian cholestasisINTRAHEPATIC ETIOLOGIESnMiscellaneousnArteriohepatic dysplasia(Alagille syndrome)nNonsyndromic paucity of intrahepatic bile ductsnCarolis diseasenBylers disease,PFICnCongenital hepatic fibrosisCOMMON ETIOLOGIESnPremature infantsnSepsis/Acidosi

9、snTPN-associatednDrug-inducednIdiopathic neonatal hepatitisnExtrahepatic biliary atresianAlpha-1-antitrypsin deficiencynIntrahepatic cholestasis syndromesCLINICAL PRESENTATIONnJaundicenScleral icterusnHepatomegalynAcholic stoolsnDark urinenOther signs and symptoms depend on specific disease processG

10、OALS OF TIMELY EVALUATIONnDiagnose and treat known medical and/or life-threatening conditions.nIdentify disorders amenable to surgical therapy within an appropriate time-frame.nAvoid surgical intervention in intrahepatic diseases.BuBc BuBuHemolysis Rh ABOBreast MilkPhysiologicalHypothyroidismBc Buda

11、rk urineacholic stoolsBc BuBEWARE!dark urineacholic stools hepatosplenomegaly bilirubinuria conjugated bilirubin abnormal LFTsEVALUATIONnBasic evaluationnHistory and physical examination(includes exam of stool color)nCBC and reticulocyte countnElectrolytes,BUN,creatinine,calcium,phosphatenSGOT,SGPT,

12、GGT,alkaline phosphatasenTotal and direct bilirubinnTotal protein,albumin,cholesterol,PT/PTTEVALUATIONnTests for infectious causesnIndicated cultures of blood,urine,CSFnTORCH titers,VDRLnUrine for CMVnHepatitis B and C serologynOphthalmologic examinationEVALUATIONnMetabolic work-upEVALUATIONnRadiolo

13、gical evaluationEVALUATIONnInvasive studiesESTIMATED FREQUENCY OF VARIOUSCLINICAL FORMS OF NEONATALCHOLESTASISPROPOSED SUBTYPES OF INTRAHEPATICCHOLESTASISnintrahepatic or extrahepatic ntreatable disorder nliver damage ncomplications of cholestasis Investigation of CholestasisObjectivesInvestigation

14、of CholestasisInvestigation of CholestasisInvestigation of CholestasisEndoscopic Retrograde CholangioPancreatographyInvestigation of CholestasisBiliary Atresian Definition-Progressive scarring of bile ducts outside and inside of the liver that leads to complete blockage of bile flow in the first thr

15、ee months of life.Anatomy in Biliary AtresiaKasai ProcedureKASAI PROCEDUREnPerformed for biliary atresia that is not surgically correctable with excision of a distal atretic segment.nRoux-en-Y portoenterostomynBile flow re-established in 80-90%if performed prior to 8 weeks-old.nBile flow re-establis

16、hed in less than 20%if performed after 12 weeks-oldKASAI PROCEDUREnSuccess of the operation is dependent on the presence and size of ductal remnants,the extent of the intrahepatic disease,and the experience of the surgeon.nComplications are ascending cholangitis and reobstruction as well as failure

17、to re-establish bile flow.LIVER TRANSPLANTATIONnSurvival rates approach 80%at 1 year and 70%at 5 years.nBiliary atresia is the most common indication for transplant and may be the initial treatment when detected late or may be used as a salvage procedure for a failed Kasai.nUsed early in cases of ty

18、rosinemia.Outcome after Kasai procedurenShort-term-bile flow dependent on age at Kasai 90 days 10-20%nLong-term-10 yr.survival(no transplant)20-40%US,France 50%JapannLiver transplantation-required for 80%nextrahepatic biliary atresiaExtrahepatic Neonatal Cholestasis ncholedochal cystninspissated bil

19、e syndromenbile duct stenosisnspontaneous perforation of bile duct ncholelithiasisntumors,massesPersistent Familial Intrahepatic Cholestasisnormal gGThigh gGTPFIC 1nAmishPFIC 2nMiddle EasternPFIC 318q21222q24enignecurrentntrahepaticholestasisntrahepaticholestasisregnancy7q21 basolateral membrane jun

20、ctional complex apical membranehepatocytehepatocytecanaliculussinusoidsinusoidnratelimitingnagainst concentration gradient(x1000 for bile salts)nenergy requiring basolateral membrane apical membraneBSBSH2Obile saltdependent bile flowbile saltindependentbile flowNTCPNa+BSNa+/K+ATPaseK+Na+Na+Taurochol

21、ateCotransporting PolypeptideBile Salt UptakeNa+dependentNa+independentOATPsABS,OAdrugsOrganicAnionTransportingPolypeptidesNTCPNa+BSNa+/K+ATPaseK+Na+Na+TaurocholateCotransporting PolypeptideBile Salt UptakeNa+independentNa+dependentOATPsABS,OAdrugsOCT1OrganicCationTransporterOC+NTCPNa+BSNa+/K+ATPase

22、K+Na+OATPsABS,OAdrugsOCT1OrganicAnionTransporting PolypeptidesNa+Taurocholate Cotransporting PolypeptideOrganicCationTransporterOC+NTCPNa+BSNa+/K+ATPaseK+Na+OATPsABS,OAdrugsOCT1OrganicAnionTransporting PolypeptidesNa+Taurocholate Cotransporting PolypeptideOC+MRPMultidrugResistanceProtein136ABCTRANSP

23、ORTERSATPBindingCassetteBSEPBSBileSaltExportPump(SGPC)(cBAT)BSEPBSMRP2AnionicConjugatescanalicularMultispecificOrganicAcidTransporterMultidrugResistanceProtein 2bilirubinGBAG,BASglutathioneSleukotriene C4drugs17bestradiolGBSEPBSPhospholipidsMDR3MRP2AnionicConjugatesMultiDrugResistancegene productBSE

24、PBSPhospholipidsMDR3MRP2AnionicConjugateshydrophobic cationsphysiological?anticancer drugsMDR1NTCPNa+/K+ATPaseOCT1OATPsBSEPMDR3MRP2AE2Cl-channelGSH transporterMDR1canaliculuscholangiocyteClCFTRAE2ClHC0FIC1P-type ATPaseAminophospholipids11bCysticFibrosisTransmembraneRegulatorPersistent Familial Intra

25、hepatic Cholestasisnormal gGTPFIC 2nMiddle Eastern2q24high gGTPFIC 1nAmishPFIC 318q2122enignecurrentntrahepaticholestasisntrahepaticholestasisregnancy7q21PFIC 2nMiddle Eastern+nneonatal hepatitisnjaundicenpruritusnnormal gGTnbile saltsin bile in plasmanpersistent,progressivenliver failure 210 yrBSEP

26、BSBileSaltExportPump(SGPC)(cBAT)BGBSBSBSEPMRP2BAGBASBSBSgGTnbile saltsin bile in plasmannormal gGTnpruritusnjaundicenhepatitisBGBileSalts 2q24 ABC B11 liverspecificnormal gGTPFIC 2nMiddle Eastern2q24PFIC 1nAmish18q2122enignecurrentntrahepaticholestasisPersistent Familial Intrahepatic Cholestasishigh

27、 gGTPFIC 3ntrahepaticholestasisregnancy7q21PhospholipidsMDR3MultiDrugResistancegene productPFIC 3nelevated gGTnneonatal hepatitisnjaundice mildernpruritusnPL:BA ratio in bilenpersistent,progressivenliver failure 210 yr 7q 21 ABC B4 phospholipid flippase/translocase liverspecificPHOSPHATIDYLCHOLINEfl

28、ippasePhospholipidsBSPLmixed micellesMDR3cholBSEPPhospholipidsBSPLmixed micellesMDR3cholBSEPPLPhospholipidsBSPLmixed micellesMDR3cholBSEPPhospholipidsMDR3BSPLMDR3cholBSEPncholangiopathyPhospholipidsMDR3PLMDR3BSEPncholangiopathygGTBSgGTgGTnhigh gGTUPTAKECONJUGATIONEXCRETIONPRODUCTIONGBB-GBBuBc BcDubi

29、n-JohnsonRotorConjugated HyperbilirubinemiaMRP2AnionicConjugatescanalicularMultispecificOrganicAcidTransporterbilirubinGBAG,BASglutathioneSMultidrugResistanceProtein 2Dubin Johnsonnconjugated hyperbilirubinemianno liver diseasennormal liver enzymesnbrownblack pigment in hepatocytesMRP2BGBGMRP3nconju

30、gated hyperbilirubinemiaB-GB-GB-B-GBcB-GBuBgsBuBguBgB-Gdark urineacholic stoolsMRP3BSEPBSMRP2BGBGMRP3nconjugated hyperbilirubinemianno cholestasisnpigment multispecific organic anion conjugate transporter ABC C2 liver,kidney,intestineOrganicAnionConjugateshigh gGTPFIC 2nMiddle EasternPFIC 32q24ntrah

31、epaticholestasisregnancy7q21Persistent Familial Intrahepatic Cholestasisnormal gGTPFIC 1nAmish18q2122enignecurrentntrahepaticholestasisFIC1P-type ATPaseAminophospholipidsPFIC 1nAmishnintermittent persistentnprogressive liver diseasen diarrhea,pancreatitis,hearing lossPFIC1 Ptype ATPase family(ion tr

32、ansport pumps)18q2122 bovine homologue aminophospholipid transport function maintenance of membrane lipid composition?expressed in cholangiocyte,hepatocyte?,intestine,pancreas,PHOSPHATIDYLSERINEBRICmutationsP motifFIC1FIC1ndiarrheanpancreatitisALPHA-1-ANTITRYPSIN DEFICIENCYnAlpha-1-antitrypsin makes

33、 up 90%of alpha-1-globulin fractionnAssociated with PiZZ(about 10-20%will have liver disease)and rarely with PiSZ and PiZ-null phenotypesnBiopsy shows hepatocellular edema,giant cell transformation,necrosis,and pseudoacinar transformation.ALPHA-1-ANTITRYPSIN DEFICIENCYnBiopsy also shows accumulation

34、 of PAS-positive,diastase-resistant globules in the cytoplasm of periportal hepatocytes.nVarying degrees of fibrosis correlate with disease prognosis.INTRAHEPATIC CHOLESTASIS SYNDROMESnIncludes several diagnostic entities.nBiopsies show cholestasis.May show paucity of intrahepatic bile ducts,giant c

35、ell transformation,and/or fibrosis.Intrahepatic Neonatal CholestasisAlagille SyndromeAlagille Syndromen1969-Alagille et al.,first reported patients with idiopathic bile duct paucity and similar clinical features including congenital heart diseasen1973-Watson&Miller recognized a syndrome that include

36、d pulmonary artery abnormalities,neonatal liver disease,somatic anomalies and a familial tendency Paucity of Bile DuctsAlagille Syndromen1975-Alagille et al.,published extended observations in 15 patients Intrahepatic Neonatal CholestasisClinical Features:HepaticnHepatomegalynNeonatal hepatitisnSple

37、nomegalynPortal hypertensionnCirrhosisnSynthetic liver failureClinical Features:HepaticClinical Features:CardiovascularClinical Features:Skeletaln“Butterfly vertebrae”nShortened interpedicular distancenShortened distal phalangesnShortened distal radius and ulna nSpina bifida occultanFusion of adjace

38、nt vertebraenClubbingnPathologic fracturesnOsteopenianRicketsnAbsent 12th ribClinical Features:SkeletalButterfly VertebrateClinical Features:OcularnPosterior embryotoxonClinical Features:OcularPosterior EmbryotoxonPosterior Embryotoxon:prominent Schwalbes line is visible just inside the temporal lim

39、bus.Alagille Syndrome:GeneticsnJAG1:StructureDefects of Bile Acid Synthesis1.7-hydroxylation of sterol precursors CTX2.ring structure modification3.side chain oxidation and shortening4.conjugation of the bile acid with an amino acid Therapy of Neonatal CholestasisTREATMENTnMedical managementTREATMENTnNutritional supportTREATMENTnNutritional support(cont.)TREATMENTnTreatment of pruritusTREATMENTnManagement of portal hypertension and its consequencesTREATMENTnManagement of portal hypertension and its consequences(cont.)REFERURGENTLYNeonatal CholestasisThank you!