婴儿郁胆分子机制初探.ppt

胆盐代谢及转运和肝内胆汁淤积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“特发性特发性”新生儿肝炎新生儿肝炎n nGGT and the outcomeJuly 1,1981-Jan 1,1985,186 July 1,1981-Jan 1,1985,186 infants,29 diagnosed as INHS,infants,29 diagnosed as INHS,followed up for at least 1 year,followed up for at least 1 year,or until death:or until death:n n17 with increased GGT 17 with increased GGT(=2.1*normal upper limit),(=2.1*normal upper limit),All but 1 in good prognosisAll but 1 in good prognosisn n12 with normal GGT,All poor 12 with normal GGT,All poor prognosisprognosisMaggiore G,et al.J Pediatr,1987;112:251-252.Maggiore G,et al.J Pediatr,1987;112:251-252.Kings病例入选标准病例入选标准n nAug 1991 to Nov 2000,Conjugated hyperbilirubinemia under 3 months of age(973 cases)n nNo specific etiologic factor can be ascertained after comprehensive work-upn nFollowed up for at least one year or until diedWang JS,Eur J Pediatr,2006,in press病例排除标准病例排除标准n n INR1.2 and not be fully corrected after vitamin K injection n nFollow up interval longer than 3 months n nOther severe congenital abnormalitiesn nG6PD deficiency n n Evidence of active CMV infection in spite of no inclusion found on liver biopsy n nUSS demonstrated bile duct dilation.Basic informationn n128 cases elected,110 biopsyedn n6 patients diagnosed as PFIC 1 or 2,1 recurred jaundice.GGT level with endpoints without GGT level with endpoints without endpointsendpointsPresentation 29-84 52.9%100Peak 36-93 13.2%50U/L50U/L组组3232例，例，3 3例预后不良例预后不良(P P=0.001)=0.001)峰值峰值 GT 100U/LGT 100U/L进行分组进行分组n n100U/L100U/L组组1010例，例，6 6例预后不良例预后不良n n100U/L100U/L组组2828例，例，2 2例预后不良例预后不良(P P=0.002)=0.002)n n血清GGT水平和预后的有关（和CMV状态无关）王中林王中林.肝脏肝脏 20052005，(4)(4)进行性家族性肝内郁胆进行性家族性肝内郁胆（PFICPFIC）n nFirst reported in Amish family(Byler disease),autosomal recessive inheritancen nClinical presentation:Cholestasis and low GGTCholestasis and low GGTPruritus,EpistaxisPruritus,EpistaxisNormal or near normal Normal or near normal cholesterol,No xanthomascholesterol,No xanthomasFIC1 deficiencyn nBRIC 基因定位18q21-22Houwen RH,1994,Nat Genet 8:380Houwen RH,1994,Nat Genet 8:380n n PFIC(Byler disease)基因定位18q21-22Carlton VE,1995,4:1049-1053Carlton VE,1995,4:1049-1053n nPFIC遗传异质性，PFIC1n nATP8B1基因，编码的产物FIC1Bull LN,Nat Genet 1998,18:219Bull LN,Nat Genet 1998,18:219FIC1 deficiency(续续)n nGreenland familial cholestasis,Asp554AsnKlomp LW,Hepatology,2000,32:1337Klomp LW,Hepatology,2000,32:1337n n各地的散发性病例无家族史、父母非近亲婚配无家族史、父母非近亲婚配欧洲、日本、中国台湾欧洲、日本、中国台湾n n新认识PFIC1PFIC1和和BRIC 1BRIC 1有同一基因引起有同一基因引起n nPFICPFIC多见缺失、移位、无义突变多见缺失、移位、无义突变n nBRICBRIC多见错义突变多见错义突变PFIC1PFIC1和和BRIC 1BRIC 1可表现为一连续过程可表现为一连续过程共同的临床特征共同的临床特征Low GGT in cholestasisLow GGT expressionDefect of bile salt exportationBSEP deficiencyn n1997年，低GGT PFIC的第二个基因（沙特）被定位于2q24，因此这种被命名为PFIC2 Strautnieks SS.Am J Hum Genet.Strautnieks SS.Am J Hum Genet.61,630.61,630.n n1998年，BSEP基因突变引起PFIC 2 Strautnieks SS.Nat Genet.20,233.Strautnieks SS.Nat Genet.20,233.n n2004 年，BRIC 2由ABCB11突变n nPFICPFIC多见缺失、移位、无义突变多见缺失、移位、无义突变,BRIC,BRIC多见错义突多见错义突变变van Mil SWC,Gastroenterology,van Mil SWC,Gastroenterology,127,379.127,379.n nPFIC 2 见于欧洲、日本、中国等世界各地Case 2 20061388 GA,A167I Case 3 CAG TAGExon 18 C2230T Q702Stop Case 5 Intron 22(+3)Exon 7 T A 562 GT G188WCase 5n nIntron 22(+3)n n紧邻剪切位点(ACCT)T to An nHum AAGATTACCTGn nMus AAGATTACCTGn nDog AAGATTACCTGn nCow TAGATTACCTGn nCase AAGATAACCTGCase 7n nIntron 6n nT+63T/Gn n(167)Low GGT in cholestasisDefect of bile salt exportationDefect of bile salt synthesisBile acid synthetic defectn n16 enzymes catalyze 17 reactions in bile acid synthesis from cholesterolRussell DW.Annu Rev Biochem 2003,72,137Russell DW.Annu Rev Biochem 2003,72,137n nDefects in different enzymes associate with neonatal cholestasisDelta(4)-3-oxosteroid 5beta-Delta(4)-3-oxosteroid 5beta-reductase(AKR1D1)reductase(AKR1D1)Gonzales E,J Hepatol 2004,40,716Gonzales E,J Hepatol 2004,40,716Oxysterol 7Oxysterol 7-hydroxylase(CRP7B1)-hydroxylase(CRP7B1)Setchell KDR,J Clin Invest 1998,102,1690Setchell KDR,J Clin Invest 1998,102,1690Bile acid synthetic defect-PFIC 4n n2000,HSD3B7,chromosome 16p12-p11.2Encoding 3-beta-hydroxy-delta-5-C27 Encoding 3-beta-hydroxy-delta-5-C27 steroid oxidoreductase(C27-3-BETA-steroid oxidoreductase(C27-3-BETA-HSD)HSD)Participate in all pathways of bile acid Participate in all pathways of bile acid synthesis(7-alpha-hydroxylated synthesis(7-alpha-hydroxylated sterols)sterols)2 bp deletion in a Saudi boy with 2 bp deletion in a Saudi boy with neonatal PICneonatal PICSchwarz M.J Clin Invest 2000,106,1175Schwarz M.J Clin Invest 2000,106,1175n n2003,confirmed in a Chilean family,a French family,a British and a Canadian familyCheng JB.J Clin Endocr Metab 2003,Cheng JB.J Clin Endocr Metab 2003,88:183388:1833对临床的意义对临床的意义n n将将PFIC和和BRIC区分出不同的类型区分出不同的类型Diarrhea,Pancreatitis Diarrhea,Pancreatitis（PFIC1)PFIC1)胆石症胆石症胆石症胆石症 （PFIC2)PFIC2)n n将将PFIC和和BRIC有机的联系在一起有机的联系在一起疾病的两极，表型可转换疾病的两极，表型可转换疾病的两极，表型可转换疾病的两极，表型可转换n nvan Ooteghem NA,J Hepatol van Ooteghem NA,J Hepatol 2002,36,4392002,36,439n n 预后判断预后判断More progressive in BSEPMore progressive in BSEPMalignancy in BSEP Malignancy in BSEP Growth retardation in FIC1Growth retardation in FIC1对临床的意义对临床的意义n nHistologyPFIC1PFIC1：Cholestasis with Cholestasis with nonspecific hepatitis,Low nonspecific hepatitis,Low expression of GGT at canalicularexpression of GGT at canalicularPFIC2PFIC2：Neonatal hepatitis Neonatal hepatitis（multinuclear giant cell multinuclear giant cell transformation)transformation)Bile acid synthetic defect:Giant Bile acid synthetic defect:Giant cell hepatitiscell hepatitis Chen HL,J Pediatr.2002,140,119Chen HL,J Pediatr.2002,140,119 Knisely AS.Perspect Pediatr Pathol 2000,3,113 Knisely AS.Perspect Pediatr Pathol 2000,3,113 Bove KE.Pediatr Dev Pathol 2004,7,315 Bove KE.Pediatr Dev Pathol 2004,7,315对临床的意义对临床的意义n nTreatmentExogenous bile acid Exogenous bile acid administrationadministrationn nCure for some bile acid synthetic Cure for some bile acid synthetic defectdefectTransplatationTransplatationn ncure the disease in BSEPcure the disease in BSEPn nOutside liver symptoms Outside liver symptoms continue(FIC1)continue(FIC1)Partial bile diversionPartial bile diversionn nD482G or E297G respond well in D482G or E297G respond well in BSEPBSEP“Transit”neonatal hepatitisn nThe remaining 103 infants were included for analysis.Median age at presentation was 40 days(range 7-87 days)n nFollow up period ranged between 315 days to 9.6 years,with a median of 873 daysn nThere were no patient deaths根据入院时GGT分组，组织学表现有区别Wang JS,Eur J Pediatr,2006,in pressGGT levels rise as bilirubin&AST levels fall.There is a wide variation in time intervals to peak and resolution of disease.This patient presented on day 10 and disease resolved by day 151.Typical biochemistry dynamic profile in“transit”patientsBiochemistry dynamic profile of patient presenting earlyBiochemistry dynamic profile of patient presenting earlypresented on day 3 with a GGT 387 IU/L and CB 83mol/Lpresented on day 3 with a GGT 387 IU/L and CB 83mol/LGGT fell to 71 IU/L on day 46 as the AST levels roseGGT fell to 71 IU/L on day 46 as the AST levels roseA second peak of GGT on day 169 as the bilirubin&AST levels A second peak of GGT on day 169 as the bilirubin&AST levels fell.fell.Children with idiopathic neonatal hepatitis have more severe disease if their presenting GGT levels are 100 IU/LHowever,the outcome appears to be good if the GGT becomes raised at a later point of diseaseFurther research is required to elucidate the cause of low GGT levels and establish the possible etiologies of idiopathic neonatal hepatitis.BSEP gene deletion in a“transit”neonatal hepatitis 病初曾有血清TB下降而GGT升高达400U/L黄疸加重而GGT下降至50U/L左右，TB和ALT持续波动，而GGT始终不高，最终于1岁前死于肝功能衰竭 结结 论论n n郁胆伴持续低郁胆伴持续低GGTGGT是是PFICPFIC的重要特征的重要特征n n入院时入院时GGTGGT水平和疾病严重程度有关水平和疾病严重程度有关n n预后良好的特发性新生儿肝炎具有典型预后良好的特发性新生儿肝炎具有典型的血清的血清GGTGGT动力学动力学n n淤胆加重而淤胆加重而GGTGGT水平下降可能是毛细胆管水平下降可能是毛细胆管水平胆盐分泌和排泄衰竭的表现水平胆盐分泌和排泄衰竭的表现n n机制的阐明分子医学的深入研究机制的阐明分子医学的深入研究