婴儿郁胆分子机制初探ppt课件.ppt

胆盐代谢及转运和肝内胆汁淤积 分子医学和临床的相互促进 王建设复旦大学附属儿科医院复旦大学儿童肝病中心 特发性 新生儿肝炎 GGTandtheoutcomeJuly1 1981 Jan1 1985 186infants 29diagnosedasINHS followedupforatleast1year oruntildeath 17withincreasedGGT 2 1 normalupperlimit Allbut1ingoodprognosis12withnormalGGT AllpoorprognosisMaggioreG etal JPediatr 1987 112 251 252 King s病例入选标准 Aug1991toNov2000 Conjugatedhyperbilirubinemiaunder3monthsofage 973cases Nospecificetiologicfactorcanbeascertainedaftercomprehensivework upFollowedupforatleastoneyearoruntildied WangJS EurJPediatr 2006 inpress 病例排除标准 INR 1 2andnotbefullycorrectedaftervitaminKinjectionFollowupintervallongerthan3monthsOtherseverecongenitalabnormalitiesG6PDdeficiencyEvidenceofactiveCMVinfectioninspiteofnoinclusionfoundonliverbiopsyUSSdemonstratedbileductdilation Basicinformation 128caseselected 110biopsyed6patientsdiagnosedasPFIC1or2 1recurredjaundice GGTlevelwithendpointswithoutendpointsPresentation29 8452 9 100Peak36 9313 2 100 ThebasicandbiochemistrycharacteristicswithendpointwithoutendpointBirthweight g 3353 33 94 932410 35 89 64 Ageofjaundicenoticed29 50 8 5913 49 1 28 BiochemistryatfirstpresentationTB mmol l 183 33 28 14159 64 9 03DB mmol l 132 17 18 81119 17 8 29AST U L 376 33 113 92196 80 19 77GGT U L 45 83 8 21165 82 14 30 PeakbiochemistryatthefirstthreemonthsoffollowupTB mmol l 264 74 06167 28 8 54AST U L 569 57 180 4238 22 24 23 GGT U L 58 71 7 43311 71 20 68 PFIC ekyy入选标准 2001年6月 2004年5月就诊于传染科诊断为婴儿肝炎综合征同时符合以下指标血清总胆红素 TB 85umol L血清结合胆红素 CB 占总胆红素 15 腹部B超 同位素肝胆显像 遗传代谢病筛查等除外先天性胆道闭锁 胆道扩张及其他先天性异常 CMV指标阳性 但无多系统受累的不除外 专科门诊随访至黄疸消退 死亡或一年以上 结果 最终有38例患者符合以上条件入院时的 GT按50U L进行分组 50U L组6例 5例预后不良 50U L组32例 3例预后不良 P 0 001 峰值 GT100U L进行分组 100U L组10例 6例预后不良 100U L组28例 2例预后不良 P 0 002 血清GGT水平和预后的有关 和CMV状态无关 王中林 肝脏2005 4 进行性家族性肝内郁胆 PFIC FirstreportedinAmishfamily Bylerdisease autosomalrecessiveinheritanceClinicalpresentation CholestasisandlowGGTPruritus EpistaxisNormalornearnormalcholesterol Noxanthomas FIC1deficiency BRIC基因定位18q21 22HouwenRH 1994 NatGenet8 380PFIC Bylerdisease 基因定位18q21 22CarltonVE 1995 4 1049 1053PFIC遗传异质性 PFIC1ATP8B1基因 编码的产物FIC1BullLN NatGenet1998 18 219 FIC1deficiency 续 Greenlandfamilialcholestasis Asp554AsnKlompLW Hepatology 2000 32 1337各地的散发性病例无家族史 父母非近亲婚配欧洲 日本 中国台湾新认识PFIC1和BRIC1有同一基因引起PFIC多见缺失 移位 无义突变BRIC多见错义突变PFIC1和BRIC1可表现为一连续过程共同的临床特征 LowGGTincholestasis LowGGTexpressionDefectofbilesaltexportation BSEPdeficiency 1997年 低GGTPFIC的第二个基因 沙特 被定位于2q24 因此这种被命名为PFIC2StrautnieksSS AmJHumGenet 61 630 1998年 BSEP基因突变引起PFIC2StrautnieksSS NatGenet 20 233 2004年 BRIC2由ABCB11突变PFIC多见缺失 移位 无义突变 BRIC多见错义突变vanMilSWC Gastroenterology 127 379 PFIC2见于欧洲 日本 中国等世界各地 Case220061388G A A167I Case3CAGTAGExon18C2230TQ702Stop Case5Intron22 3 Exon7TA562G TG188W Case5 Intron22 3 紧邻剪切位点 ACCT TtoAHumAAGATTACCTGMusAAGATTACCTGDogAAGATTACCTGCowTAGATTACCTGCaseAAGATAACCTG Case7 Intron6T 63T G 167 LowGGTincholestasis DefectofbilesaltexportationDefectofbilesaltsynthesis Bileacidsyntheticdefect 16enzymescatalyze17reactionsinbileacidsynthesisfromcholesterolRussellDW AnnuRevBiochem2003 72 137DefectsindifferentenzymesassociatewithneonatalcholestasisDelta 4 3 oxosteroid5beta reductase AKR1D1 GonzalesE JHepatol2004 40 716Oxysterol7 hydroxylase CRP7B1 SetchellKDR JClinInvest1998 102 1690 Bileacidsyntheticdefect PFIC4 2000 HSD3B7 chromosome16p12 p11 2Encoding3 beta hydroxy delta 5 C27steroidoxidoreductase C27 3 BETA HSD Participateinallpathwaysofbileacidsynthesis 7 alpha hydroxylatedsterols 2bpdeletioninaSaudiboywithneonatalPICSchwarzM JClinInvest2000 106 11752003 confirmedinaChileanfamily aFrenchfamily aBritishandaCanadianfamilyChengJB JClinEndocrMetab2003 88 1833 对临床的意义 将PFIC和BRIC区分出不同的类型Diarrhea Pancreatitis PFIC1 胆石症 PFIC2 将PFIC和BRIC有机的联系在一起疾病的两极 表型可转换vanOoteghemNA JHepatol2002 36 439预后判断MoreprogressiveinBSEPMalignancyinBSEPGrowthretardationinFIC1 对临床的意义 HistologyPFIC1 Cholestasiswithnonspecifichepatitis LowexpressionofGGTatcanalicularPFIC2 Neonatalhepatitis multinucleargiantcelltransformation Bileacidsyntheticdefect GiantcellhepatitisChenHL JPediatr 2002 140 119KniselyAS PerspectPediatrPathol2000 3 113BoveKE PediatrDevPathol2004 7 315 对临床的意义 TreatmentExogenousbileacidadministrationCureforsomebileacidsyntheticdefectTransplatationcurethediseaseinBSEPOutsideliversymptomscontinue FIC1 PartialbilediversionD482GorE297GrespondwellinBSEP Transit neonatalhepatitis Theremaining103infantswereincludedforanalysis Medianageatpresentationwas40days range7 87days Followupperiodrangedbetween315daysto9 6years withamedianof873daysTherewerenopatientdeaths 根据入院时GGT分组 组织学表现有区别 WangJS EurJPediatr 2006 inpress GGTlevelsriseasbilirubin ASTlevelsfall Thereisawidevariationintimeintervalstopeakandresolutionofdisease Thispatientpresentedonday10anddiseaseresolvedbyday151 Typicalbiochemistrydynamicprofilein transit patients Biochemistrydynamicprofileofpatientpresentingearly presentedonday3withaGGT387IU LandCB83 mol LGGTfellto71IU Londay46astheASTlevelsroseAsecondpeakofGGTonday169asthebilirubin ASTlevelsfell ChildrenwithidiopathicneonatalhepatitishavemoreseverediseaseiftheirpresentingGGTlevelsare 100IU LHowever theoutcomeappearstobegoodiftheGGTbecomesraisedatalaterpointofdiseaseFurtherresearchisrequiredtoelucidatethecauseoflowGGTlevelsandestablishthepossibleetiologies