新生兒和嬰兒膽汁淤積英文版課件

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

2、e.Conjugated bilirubin exceeds 1.5 to 2.0 mg/dl.Conjugated bilirubin generally exceeds 20% of the total bilirubin.Bilirubin ProductionBiliverdinBilirubinerythrocytehemoglobinmusclemyoglobincytochromescatalaseshemeoxygenasebiliverdinreductasereticulo-endothelial cellBilirubinAlbuminliverCO + FeHemeGS

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

4、holestasisEXTRAHEPATIC ETIOLOGIESExtrahepatic biliary atresiaCholedochal cystBile duct stenosisSpontaneous perforation of the bile ductCholelithiasisInspissated bile/mucus plugExtrinsic compression of the bile ductINTRAHEPATIC ETIOLOGIESInfectiousBacterial sepsis (E. coli, Listeriosis, Staph. aureus

5、)TORCHESHepatitis B and CVaricellaCoxsackie virusEcho virusTuberculosisINTRAHEPATIC ETIOLOGIESMetabolicDisorders of Carbohydrate MetabolismGalactosemiaFructosemiaGlycogen Storage Disease Type IVDisorders of Amino Acid MetabolismTyrosinemiaHypermethioninemiaINTRAHEPATIC ETIOLOGIESMetabolic (cont.)Dis

6、orders of Lipid MetabolismNiemann-Pick diseaseWolman diseaseGaucher diseaseCholesterol ester storage diseaseDisorders of Bile Acid Metabolism3B-hydroxysteroid dehydrogenase/isomeraseTrihydroxycoprostanic acidemiaCOMMON ETIOLOGIESPremature infantsSepsis/AcidosisTPN-associatedDrug-inducedIdiopathic ne

7、onatal hepatitisExtrahepatic biliary atresiaAlpha-1-antitrypsin deficiencyIntrahepatic cholestasis syndromesCLINICAL PRESENTATIONJaundiceScleral icterusHepatomegalyAcholic stoolsDark urineOther signs and symptoms depend on specific disease processGOALS OF TIMELY EVALUATIONDiagnose and treat known me

8、dical and/or life-threatening conditions.Identify disorders amenable to surgical therapy within an appropriate time-frame. Avoid surgical intervention in intrahepatic diseases.BuHemolysisRhABOBreast MilkPhysiologicalHypothyroidismBc Budark urineacholic stoolsBc BuBEWARE!dark urineacholic stoolshepat

9、osplenomegalybilirubinuriaconjugated bilirubin abnormal LFTsEVALUATIONBasic evaluationHistory and physical examination (includes exam of stool color)CBC and reticulocyte countElectrolytes, BUN, creatinine, calcium, phosphateSGOT, SGPT, GGT, alkaline phosphataseTotal and direct bilirubinTotal protein

10、, albumin, cholesterol, PT/PTTEVALUATIONTests for infectious causesIndicated cultures of blood, urine, CSFTORCH titers, VDRLUrine for CMVHepatitis B and C serologyOphthalmologic examinationEVALUATIONMetabolic work-upProtein electrophoresis, alpha-1-antitrypsin level and phenotypeThyroid function tes

11、tsSweat chlorideUrine/serum amino acidsReview results of newborn metabolic screenUrine reducing substancesUrine bile acidsEVALUATIONRadiological evaluationUltrasonographyPatient should be NPO to increase likelihood of visualizing the gallbladder Feeding with exam may demonstrate a functioning gallbl

12、adderHepatobiliary scintigraphyPremedicate with phenobarbital 5mg/kg/d for 3-5 daysEVALUATIONInvasive studiesDuodenal intubationPercutaneous liver biopsyPercutaneous transhepatic cholangiographyEndoscopic retrograde cholangiopancreatography (ERCP)Exploratory laparotomy with intraoperative cholangiog

13、ramESTIMATED FREQUENCY OF VARIOUSCLINICAL FORMS OF NEONATALCHOLESTASISPROPOSED SUBTYPES OF INTRAHEPATICCHOLESTASISintrahepatic or extrahepatic ?treatable disorder ?liver damage ?complications of cholestasis ?Investigation of CholestasisObjectivesX-rayspine: butterfly vertebrae (Alagille)skull, long

14、bones (intrauterine infection)sweat test (cystic fibrosis)ophthalmological examinationcataract (galactosemia, intrauterine infection)retinopathy (intrauterine infection)posterior embryotoxon (Alagille)othersbone marrow (Niemann Pick disease type C)bile acidsInvestigation of CholestasisSpecial Testsu

15、ltrasoundcholedochal cyst etc.post-prandial contraction of gall bladderhepatobiliary scan (99mTc - H / B / DIS / PIP / - IDA) after pre-treatment with phenobarb or cholestyramineInvestigation of CholestasisSpecial Tests (cont)ultrasoundcholedochal cyst etc.post-prandial contraction of gall bladderhe

16、patobiliary scan (99mTc - H / B / DIS / PIP / - IDA) after pre-treatment with phenobarb or cholestyramineERCP (endoscopic retrograde cholangiopancreatography) Investigation of CholestasisSpecial Tests (cont)Endoscopic Retrograde Cholangio-PancreatographyInvestigation of CholestasisSpecial Tests (con

17、t)liver histology (needle biopsy)biliary atresia: portal ductal proliferationneonatal hepatitis: giant cellsspecific disorder e.g a1-antitrypsin Biliary Atresia Definition - Progressive scarring of bile ducts outside and inside of the liver that leads to complete blockage of bile flow in the first t

18、hree months of life. Bile is the yellow fluid made in the liver that helps digest food (fat) in the intestineAnatomy in Biliary AtresiaKasai ProcedureKASAI PROCEDUREPerformed for biliary atresia that is not surgically correctable with excision of a distal atretic segment.Roux-en-Y portoenterostomyBi

19、le flow re-established in 80-90% if performed prior to 8 weeks-old.Bile flow re-established in less than 20% if performed after 12 weeks-oldKASAI PROCEDURESuccess of the operation is dependent on the presence and size of ductal remnants, the extent of the intrahepatic disease, and the experience of

20、the surgeon.Complications are ascending cholangitis and reobstruction as well as failure to re-establish bile flow.LIVER TRANSPLANTATIONSurvival rates approach 80% at 1 year and 70% at 5 years.Biliary atresia is the most common indication for transplant and may be the initial treatment when detected

21、 late or may be used as a salvage procedure for a failed Kasai.Used early in cases of tyrosinemia.Outcome after Kasai procedureShort-term - bile flow dependent on age at Kasai 90 days 10-20%Long-term - 10 yr. survival (no transplant)20 - 40% US,France 50% JapanLiver transplantation - required for 80

22、% extrahepatic biliary atresiaExtrahepatic Neonatal Cholestasis choledochal cystinspissated bile syndromebile duct stenosisspontaneous perforation of bile duct cholelithiasistumors, massesPersistent Familial Intrahepatic Cholestasisnormal gGThigh gGTPFIC 1Byler DiseaseAmishPFIC 2Byler SyndromeMiddle

23、 EasternPFIC 318q21-222q24BenignRecurrentIntrahepaticCholestasisIntrahepaticCholestasisPregnancy7q21 basolateral membrane junctional complex apical membranehepatocytehepatocytecanaliculussinusoidsinusoidrate-limitingagainst concentration gradient (x1000 for bile salts)energy requiring basolateral me

24、mbrane apical membraneBSBSH2Obile salt-dependent bile flowbile salt-independentbile flowNTCPNa+BS-Na+/K+ ATPaseK+Na+Na+TaurocholateCotransporting PolypeptideBile Salt UptakeNa+-dependentNa+-independentOATPsA-BS-,OA-drugsOrganicAnionTransportingPolypeptidesNTCPNa+BS-Na+/K+ ATPaseK+Na+Na+TaurocholateC

25、otransporting PolypeptideBile Salt UptakeNa+-independentNa+-dependentOATPsA-BS-,OA-drugsOCT1OrganicCationTransporterOC+NTCPNa+BS-Na+/K+ ATPaseK+Na+OATPsA-BS-,OA-drugsOCT1OrganicAnionTransporting PolypeptidesNa+ Taurocholate Cotransporting PolypeptideOrganicCationTransporterOC+NTCPNa+BS-Na+/K+ ATPase

26、K+Na+OATPsA-BS-,OA-drugsOCT1OrganicAnionTransporting PolypeptidesNa+ Taurocholate Cotransporting PolypeptideOC+MRPMulti-drugResistanceProtein136ABCTRANSPORTERSATPBindingCassetteBSEPBS-BileSaltExportPump(SGPC)(cBAT)BSEPBS-MRP2AnionicConjugatescanalicularMulti-specificOrganicAcidTransporterMulti-drugR

27、esistanceProtein 2bilirubin-GBA-G, BA-Sglutathione-Sleukotriene C4drugs17b-estradiol-GBSEPBS-PhospholipidsMDR3MRP2AnionicConjugatesMultiDrugResistancegene productBSEPBS-PhospholipidsMDR3MRP2AnionicConjugateshydrophobic cationsphysiological?anti-cancer drugsMDR1NTCPNa+/K+ATPaseOCT1OATPsBSEPMDR3MRP2AE

28、2Cl-channelGSH transporterMDR1canaliculuscholangiocyteCl-CFTRAE2Cl-HC0-FIC1P-type ATPaseAminophospholipids11bCysticFibrosisTransmembraneRegulatorPersistent Familial Intrahepatic Cholestasisnormal gGTPFIC 2Byler SyndromeMiddle Eastern2q24high gGTPFIC 1Byler DiseaseAmishPFIC 318q21-22BenignRecurrentIn

29、trahepaticCholestasisIntrahepaticCholestasisPregnancy7q21PFIC 2Byler SyndromeMiddle Eastern +neonatal hepatitisjaundicepruritusnormal gGTbile salts in bile in plasmapersistent, progressiveliver failure 2-10 yrBSEPBSBileSaltExportPump(SGPC)(cBAT)B-GBSBSBSEPMRP2BA-GBA-SBSBSgGTbile salts in bile in pla

30、smanormal gGTpruritusjaundicehepatitisB-GBileSalts2q24ABC B11liver-specificnormal gGTPFIC 2Byler SyndromeMiddle Eastern2q24PFIC 1Byler DiseaseAmish18q21-22BenignRecurrentIntrahepaticCholestasisPersistent Familial Intrahepatic Cholestasishigh gGTPFIC 3IntrahepaticCholestasisPregnancy7q21Phospholipids

31、MDR3MultiDrugResistancegene productPFIC 3elevated gGTneonatal hepatitisjaundice milderpruritusPL : BA ratio in bilepersistent, progressiveliver failure 2-10 yr7q 21ABC B4phospholipid flippase/translocaseliver-specificPHOSPHATIDYLCHOLINEflippasePhospholipidsBSPLmixed micellesMDR3cholBSEPPhospholipids

32、BSPLmixed micellesMDR3cholBSEPPLPhospholipidsBSPLmixed micellesMDR3cholBSEPPhospholipidsMDR3BSPLMDR3cholBSEPcholangiopathybile duct proliferationportal inflammationfibrosisPhospholipidsMDR3PLMDR3BSEPcholangiopathybile duct proliferationportal inflammationfibrosisgGTBSgGTgGThigh gGTUPTAKECONJUGATIONE

33、XCRETIONPRODUCTIONGBB-GBBuBcBcDubin-JohnsonRotorConjugated HyperbilirubinemiaMRP2AnionicConjugatescanalicularMulti-specificOrganicAcidTransporterbilirubin-GBA-G, BA-Sglutathione-SMulti-drugResistanceProtein 2Dubin Johnsonconjugated hyperbilirubinemiano liver diseasenormal liver enzymesbrown-black pi

34、gment in hepatocytesMRP2B-GB-GMRP3conjugated hyperbilirubinemiaB-GB-GB-B-GBcB-GBuBgsBuBguBgB-Gdark urineacholic stoolsMRP3BSEPBSMRP2B-GB-GMRP3conjugated hyperbilirubinemiano cholestasispigmentmulti-specific organic anion conjugate transporterABC C2liver, kidney, intestineOrganicAnionConjugateshigh g

35、GTPFIC 2Byler SyndromeMiddle EasternPFIC 32q24IntrahepaticCholestasisPregnancy7q21Persistent Familial Intrahepatic Cholestasisnormal gGTPFIC 1Byler DiseaseAmish18q21-22BenignRecurrentIntrahepaticCholestasisFIC1P-type ATPaseAminophospholipidsPFIC 1Byler DiseaseAmishintermittent persistentprogressive

36、liver disease diarrhea, pancreatitis, hearing lossPFIC1P-type ATPase family (ion transport pumps)18q21-22 bovine homologue -aminophospholipid transportfunction - maintenance of membrane lipid composition?expressed in cholangiocyte, hepatocyte?, intestine, pancreas, PHOSPHATIDYLSERINEBRICmutationsP m

37、otifFIC1FIC1diarrheapancreatitisALPHA-1-ANTITRYPSIN DEFICIENCYAlpha-1-antitrypsin makes up 90% of alpha-1-globulin fractionAssociated with PiZZ (about 10-20% will have liver disease) and rarely with PiSZ and PiZ-null phenotypesBiopsy shows hepatocellular edema, giant cell transformation, necrosis, a

38、nd pseudoacinar transformation.ALPHA-1-ANTITRYPSIN DEFICIENCYBiopsy also shows accumulation of PAS-positive, diastase-resistant globules in the cytoplasm of periportal hepatocytes.Varying degrees of fibrosis correlate with disease prognosis.INTRAHEPATIC CHOLESTASIS SYNDROMESIncludes several diagnost

39、ic entities.Biopsies show cholestasis. May show paucity of intrahepatic bile ducts, giant cell transformation, and/or fibrosis.Paucity of intrahepatic bile ductsIntrahepatic Neonatal CholestasisAlagille SyndromeAlagille Syndrome1969-Alagille et al., first reported patients with idiopathic bile duct

40、paucity and similar clinical features including congenital heart disease1973-Watson & Miller recognized a syndrome that included pulmonary artery abnormalities, neonatal liver disease, somatic anomalies and a familial tendency Coined term arteriohepatic dysplasiaPaucity of Bile DuctsAlagille Syndrom

41、e1975-Alagille et al., published extended observations in 15 patients Chronic liver diseaseCharacteristic faciesSystolic murmurVertebral arch defectsMental retardation, hypgonadism,Family historyPaucity of intrahepatic bile ductsAlagille syndromenon-syndromicIntrahepatic Neonatal CholestasisClinical

42、 Features: HepaticHepatomegalyNeonatal hepatitisSplenomegalyPortal hypertensionCirrhosisSynthetic liver failureClinical Features: HepaticCholestasisJaundiceConjugated hyperbilirubinemia in neonatal periodPruritisXanthomasBiochemical abnormalitiesClinical Features: CardiovascularMurmurMost common car

43、diac manifestation of AGSDue to stenosis at some level in the pulmonary tree with or without structural cardiac diseaseClinical Features: Skeletal“Butterfly vertebrae”Shortened interpedicular distanceShortened distal phalangesShortened distal radius and ulna Spina bifida occultaFusion of adjacent ve

44、rtebraeClubbingPathologic fracturesOsteopeniaRicketsAbsent 12th ribClinical Features: SkeletalButterfly VertebrateClinical Features: OcularPosterior embryotoxonAn abnormal prominence of Schwalbes linePresent in 56-95% of AGS patientsSeen in 8-15% of general populationClinical Features: OcularPosteri

45、or EmbryotoxonPosterior Embryotoxon: prominent Schwalbes line is visible just inside the temporal limbus. Alagille Syndrome: GeneticsJAG1: StructureExtracellular domain21 amino acid signal peptide40 amino acide DSL region16 EGF-like regionsCysteine rich regionTransmembrane domainIntracellular domainDefects of Bile Acid Synthesis1. 7-hydroxylation of sterol precursors CTX2. ring structure modification3. side chain oxidation and short