嬰兒郁膽分子機(jī)制初探課件

1、膽鹽代謝及轉(zhuǎn)運(yùn)和肝內(nèi)膽汁淤積 分子醫(yī)學(xué)和臨床的相互促進(jìn) 王建設(shè)復(fù)旦大學(xué)附屬兒科醫(yī)院復(fù)旦大學(xué)兒童肝病中心“特發(fā)性”新生兒肝炎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病例入選標(biāo)準(zhǔn)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病例排除標(biāo)準(zhǔn) 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組32例，3例預(yù)后不良(P=0.001)峰值GT 100U/L進(jìn)行分組100U/L組10例，6例預(yù)后不良100U/L組28例，2例預(yù)后不良(P=0.002)血清GGT水平和預(yù)后的有關(guān)（和CMV狀態(tài)無(wú)關(guān)）王中林. 肝臟 2005，(4)進(jìn)行性家族

5、性肝內(nèi)郁膽（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遺傳異質(zhì)性，PFIC1ATP8B1基因，編碼的產(chǎn)物FIC1Bull LN, Nat Genet 1998, 18:219FIC1 deficiency (續(xù))Greenland familial cholestasis, Asp554AsnKlomp LW, Hepatology, 2000,32:1337各地的散發(fā)性病例無(wú)家族史、父母非近親婚配歐洲、日本、中國(guó)臺(tái)灣新認(rèn)識(shí)PFIC1和BRIC 1有同一基因引起PFIC多見缺失、移位、無(wú)義突變BRIC多見錯(cuò)義突變PFIC1和BRIC 1可表現(xiàn)為一連續(xù)過程共同的臨床特征Low GGT i

7、n cholestasisLow GGT expressionDefect of bile salt exportationBSEP deficiency1997年，低GGT PFIC的第二個(gè)基因（沙特）被定位于2q24，因此這種被命名為PFIC2 Strautnieks SS. Am J Hum Genet. 61,630.1998年， BSEP基因突變引起PFIC 2 Strautnieks SS. Nat Genet. 20,233.2004 年，BRIC 2由ABCB11突變PFIC多見缺失、移位、無(wú)義突變, BRIC多見錯(cuò)義突變van Mil SWC, Gastroenterolog

8、y, 127,379.PFIC 2 見于歐洲、日本、 中國(guó)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)緊鄰剪切位點(diǎn)(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對(duì)臨床的意義將PFIC和BRIC區(qū)分出不同的類型Diarrhea, Pancrea

12、titis （PFIC1)膽石癥 （PFIC2)將PFIC和BRIC有機(jī)的聯(lián)系在一起疾病的兩極，表型可轉(zhuǎn)換van Ooteghem NA, J Hepatol 2002,36,439 預(yù)后判斷More progressive in BSEPMalignancy in BSEP Growth retardation in FIC1對(duì)臨床的意義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對(duì)臨床的意義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根據(jù)入院時(shí)GGT分組，組織學(xué)表現(xiàn)有區(qū)別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