婴儿郁胆分子机制初探课件

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 progno

2、sisMaggiore 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 diedWang JS, Eur J Pediatr, 2006, in

3、 press病例排除标准 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 information1

4、28 cases 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%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

5、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 xanthomasFIC1 deficiencyBRIC 基因定位18q21-22Houwen RH, 1994, Nat Genet 8:380 PFIC (Byler disease)基因定位18q21-22Ca

6、rlton VE, 1995, 4:1049-1053PFIC遗传异质性，PFIC1ATP8B1基因，编码的产物FIC1Bull LN, Nat Genet 1998, 18:219FIC1 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 i

7、n cholestasisLow GGT expressionDefect of bile salt exportationBSEP deficiency1997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 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, Gastroenterolog

8、y, 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 G188WCase 5Intron 22 (+3)紧邻剪切位点(ACCT) T to AHum AAGATTACCTGMus AAGATTACCTGDog AAGATTACCTGCow TAGATTACCTGCase AAGATAACCTGCase 7Intron 6T+63T/G (167) Low GGT in cho

9、lestasisDefect of bile salt exportationDefect of bile salt synthesisBile acid synthetic defect16 enzymes catalyze 17 reactions in bile acid synthesis from cholesterolRussell DW. Annu Rev Biochem 2003,72,137Defects in different enzymes associate with neonatal cholestasisDelta(4)-3-oxosteroid 5beta-re

10、ductase(AKR1D1)Gonzales E, J Hepatol 2004,40,716Oxysterol 7-hydroxylase (CRP7B1)Setchell KDR, J Clin Invest 1998,102,1690Bile acid synthetic defect -PFIC 42000, HSD3B7, chromosome 16p12-p11.2Encoding 3-beta-hydroxy-delta-5-C27 steroid oxidoreductase (C27-3-BETA-HSD)Participate in all pathways of bil

11、e 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 2003, 88:1833对临床的意义将PFIC和BRIC区分出不同的类型Diarrhea, Pancrea

12、titis （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 at canalicularPFIC2：Neonatal hepatitis （multinuclear

13、 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 some bile acid synthetic defectTransplatationcur

14、e the disease in BSEPOutside liver symptoms continue(FIC1)Partial bile diversionD482G or E297G respond well in BSEP“Transit”neonatal hepatitisThe remaining 103 infants were included for analysis. Median age at presentation was 40 days (range 7 - 87 days)Follow up period ranged between 315 days to 9.

15、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 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

16、by day 151.Typical biochemistry dynamic profile in “transit”patientsBiochemistry dynamic profile of patient presenting earlypresented 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 169 as the bilirubin & AST levels fell.Chil

17、dren 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