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 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 diedWang JS, Eur J Pediatr, 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.Basic 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%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 xanthomasFIC1 deficiency BRIC 基因定位18q21-22 Houwen RH, 1994, Nat Genet 8:380 PFIC (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, 18:219FIC1 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 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 cholestasisLow GGT expressionDefect of bile salt exportationBSEP 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 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 TAG Exon 18 C2230T Q702Stop Case 5Intron 22 (+3) Exon 7T A 562 GT G188WCase 5 Intron 22 (+3) 紧邻剪切位点(ACCT) T to A Hum AAGATTACCTG Mus AAGATTACCTG Dog AAGATTACCTG Cow TAGATTACCTG Case AAGATAACCTGCase 7 Intron 6 T+63T/G (167) Low GGT in cholestasisDefect of bile salt exportationDefect of bile salt synthesisBile acid synthetic defect 16 enzymes catalyze 17 reactions in bile acid synthesis from cholesterolRussell DW. Annu Rev Biochem 2003,72,137 Defects in different 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 1998,102,1690Bile acid synthetic defect -PFIC 4 2000, HSD3B7, chromosome 16p12-p11.2 Encoding 3-beta-hydroxy-delta-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 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, 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对临床的意义 Treatment Exogenous bile acid administration Cure for some bile acid synthetic defect Transplatation cure the disease in BSEP Outside liver symptoms continue(FIC1) Partial bile diversion D482G 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) Follow up period ranged between 315 days to 9.6 years, with a median of 873 days There 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 pr