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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 outcome July 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 prognosis 12 with normal GGT, All poor
2、 prognosisMaggiore 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-up Followed up for at least one year or until died,Wang JS, Eur J Pedia
3、tr, 2006, in 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 abnormalities G6PD deficiency Evidence of active CMV infection in spite of no inclusion found on liver biopsy USS demonstrated bile duct dilation.,Bas
4、ic information,128 cases elected, 110 biopsyed 6 patients diagnosed as PFIC 1 or 2, 1 recurred jaundice.GGT level with endpoints without endpoints Presentation 29-84 52.9%100 Peak 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
5、） 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 inheritance Clinical presentation: Cholestasis and low GGT Pruritus, Epistaxis Normal or near normal cholesterol, No xanthomas,FIC1 deficiency,BRIC 基因定位18q21-22 Houwen RH, 1994, Nat Genet 8:380PFI
6、C (Byler disease)基因定位18q21-22 Carlton VE, 1995, 4:1049-1053 PFIC遗传异质性，PFIC1 ATP8B1基因，编码的产物FIC1 Bull LN, Nat Genet 1998, 18:219,FIC1 deficiency (续),Greenland familial cholestasis, Asp554Asn Klomp 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 BR
7、IC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 expression Defect 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 2Strautnieks SS. Nat Genet. 20,233. 2004 年，BRIC 2由ABCB11突变 PF
8、IC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 TAG Exon 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 A Hum AAGATTACCTG Mus AAGATTACCTG Dog AAGATTACCTG Cow TAGA
9、TTACCTG Case AAGATAACCTG,Case 7,Intron 6 T+63T/G(167),Low GGT in cholestasis,Defect of bile salt exportation Defect of bile salt synthesis,Bile acid synthetic defect,16 enzymes catalyze 17 reactions in bile acid synthesis from cholesterol Russell DW. Annu Rev Biochem 2003,72,137 Defects in different
10、 enzymes associate with neonatal cholestasis Delta(4)-3-oxosteroid 5beta-reductase(AKR1D1) Gonzales E, J Hepatol 2004,40,716 Oxysterol 7-hydroxylase (CRP7B1) Setchell KDR, J Clin Invest 1998,102,1690,Bile acid synthetic defect -PFIC 4,2000, HSD3B7, chromosome 16p12-p11.2 Encoding 3-beta-hydroxy-delt
11、a-5-C27 steroid oxidoreductase (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 PIC Schwarz M. J Clin Invest 2000,106,1175 2003, confirmed in a Chilean family, a French family, a British and a Canadian famil
12、y Cheng 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, 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 BSEP Malignancy in BSEP Growth retardation in FIC1,对临床的意义,Histology PFIC1：Cholestasis with nonspecific hepatitis, Low expression of GGT at canalicular PFIC2：Neonatal hepatitis （multinuclear giant cell transformation) Bile acid synthetic defect: Giant cell hepatitisChen HL, J Pediatr. 2002,140,119Knisely AS. Perspect Pediatr Pathol 2000,3,113Bove KE. Pediatr Dev Pathol 2004,7,315,
