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1、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,GGT and the outcomeJuly 1,1981-Jan 1,1985,186 infants,29 diagnosed as INHS,followed up for at least 1 year,or until death:17 with increased GGT(=2.1*normal upper limit),All but 1 in good prognosis12 with normal GGT,All poor prognosisMagg
2、iore G,et al.J Pediatr,1987;112:251-252.,Kings病例入选标准,Aug 1991 to Nov 2000,Conjugated hyperbilirubinemia under 3 months of age(973 cases)No specific etiologic factor can be ascertained after comprehensive work-upFollowed up for at least one year or until died,Wang JS,Eur J Pediatr,2006,in press,病例排除标
3、准,INR1.2 and not be fully corrected after vitamin K injection Follow up interval longer than 3 months Other severe congenital abnormalitiesG6PD deficiency Evidence of active CMV infection in spite of no inclusion found on liver biopsy USS demonstrated bile duct dilation.,Basic information,128 cases
4、elected,110 biopsyed6 patients diagnosed as PFIC 1 or 2,1 recurred jaundice.GGT level with endpoints without endpointsPresentation 29-84 52.9%100Peak 36-93 13.2%100,The basic and biochemistry characteristics with endpoint without endpointBirth weight(g)3353.3394.93 2410.3589.64*Age of jaundice notic
5、ed 29.508.59 13.491.28*Biochemistry at first presentationTB(mmol/l)183.3328.14 159.649.03DB(mmol/l)132.1718.81 119.178.29AST(U/L)376.33113.92 196.8019.77GGT(U/L)45.838.21 165.8214.30*Peak biochemistry at the first three months of follow upTB(mmol/l)26474.06 167.288.54AST(U/L)569.57180.4 238.2224.23*
6、GGT(U/L)58.717.43 311.7120.68*,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GT 100U/L进行分组100U/L组10
7、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）,First reported in Amish family(Byler disease),autosomal recessive inheritanceClinical presentation:Cholestasis and low GGTPruritus,EpistaxisNormal or near normal cholesterol,No xanthomas,FIC1 deficiency,BRIC 基因
8、定位18q21-22Houwen RH,1994,Nat Genet 8:380 PFIC(Byler disease)基因定位18q21-22Carlton VE,1995,4:1049-1053PFIC遗传异质性，PFIC1ATP8B1基因，编码的产物FIC1Bull LN,Nat Genet 1998,18:219,FIC1 deficiency(续),Greenland familial cholestasis,Asp554AsnKlomp LW,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BRIC 1有同
9、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BRIC 1可表现为一连续过程共同的临床特征,Low GGT in cholestasis,Low GGT expressionDefect of bile salt exportation,BSEP deficiency,1997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.61,630.1998年，BSEP基因突变引起PFIC 2 Strautnieks SS.Nat Genet.20,233.2004 年，BRIC
10、 2由ABCB11突变PFIC多见缺失、移位、无义突变,BRIC多见错义突变van Mil SWC,Gastroenterology,127,379.PFIC 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 G188W,Case 5,Intron 22(+3)紧邻剪切位点(ACCT)T to AHum AAGATTACCTGMus AAGATTACCTGDog AAGATTACCTGCow TAGATTAC
11、CTGCase AAGATAACCTG,Case 7,Intron 6T+63T/G(167),Low GGT in cholestasis,Defect of bile salt exportationDefect of bile salt synthesis,Bile acid synthetic defect,16 enzymes catalyze 17 reactions in bile acid synthesis from cholesterolRussell DW.Annu Rev Biochem 2003,72,137Defects in different enzymes a
12、ssociate with neonatal cholestasisDelta(4)-3-oxosteroid 5beta-reductase(AKR1D1)Gonzales E,J Hepatol 2004,40,716Oxysterol 7-hydroxylase(CRP7B1)Setchell KDR,J Clin Invest 1998,102,1690,Bile acid synthetic defect-PFIC 4,2000,HSD3B7,chromosome 16p12-p11.2Encoding 3-beta-hydroxy-delta-5-C27 steroid oxido
13、reductase(C27-3-BETA-HSD)Participate in all pathways of bile acid synthesis(7-alpha-hydroxylated sterols)2 bp deletion in a Saudi boy with neonatal PICSchwarz M.J Clin Invest 2000,106,11752003,confirmed in a Chilean family,a French family,a British and a Canadian familyCheng JB.J Clin Endocr Metab 2
14、003,88:1833,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van Ooteghem NA,J Hepatol 2002,36,439 预后判断More progressive in BSEPMalignancy in BSEP Growth retardation in FIC1,对临床的意义,HistologyPFIC1：Cholestasis with nonspecific hepatitis,Low expression of GGT a
15、t canalicularPFIC2：Neonatal hepatitis（multinuclear giant cell transformation)Bile acid synthetic defect:Giant cell hepatitis Chen HL,J Pediatr.2002,140,119 Knisely AS.Perspect Pediatr Pathol 2000,3,113 Bove KE.Pediatr Dev Pathol 2004,7,315,对临床的意义,TreatmentExogenous bile acid administrationCure for s
16、ome bile acid synthetic defectTransplatationcure the disease in BSEPOutside liver symptoms continue(FIC1)Partial bile diversionD482G or E297G respond well in BSEP,“Transit”neonatal hepatitis,The remaining 103 infants were included for analysis.Median age at presentation was 40 days(range 7-87 days)F
17、ollow up period ranged between 315 days to 9.6 years,with a median of 873 daysThere 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 press,GGT levels rise as bilirubin&AST levels fall.There is a wide variation in time intervals to peak and resolution of disease.This patient p
18、resented on day 10 and disease resolved by day 151.,Typical biochemistry dynamic profile in“transit”patients,Biochemistry dynamic profile of patient presenting early,presented 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 roseA second peak of GGT on day 1
19、69 as the bilirubin&AST levels 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
20、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 论,郁胆伴持续低GGT是PFIC的重要特征入院时GGT水平和疾病严重程度有关预后良好的特发性新生儿肝炎具有典型的血清GGT动力学淤胆加重而GGT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机制的阐明分子医学的深入研究,THANK YOU,
