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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、 prognosis Maggiore 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 Pedi
3、atr, 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.,Ba
4、sic 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%100,The basic and biochemistry characteristics with endpoint without endpoint Birth weight (g) 3353.3394.93
5、 2410.3589.64* Age of jaundice noticed 29.508.59 13.491.28* Biochemistry at first presentation TB (mmol/l) 183.3328.14 159.649.03 DB (mmol/l) 132.1718.81 119.178.29 AST (U/L) 376.33113.92 196.8019.77 GGT (U/L) 45.838.21 165.8214.30* Peak biochemistry at the first three months of follow up TB (mmol/l
6、) 26474.06 167.288.54 AST (U/L) 569.57180.4 238.2224.23* 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
7、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,
8、 Epistaxis Normal or near normal cholesterol, No xanthomas,FIC1 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, 18:219,FIC1 deficiency (续),Greenland familial chole
9、stasis, 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 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
10、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 5 Intron
11、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 TAGATTACCTG 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
12、enzymes catalyze 17 reactions in bile acid synthesis from cholesterol Russell 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 KD
13、R, J Clin Invest 1998,102,1690,Bile 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 neona
14、tal PIC Schwarz M. J Clin Invest 2000,106,1175 2003, confirmed in a Chilean family, a French family, a British and a Canadian family 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 Hepa
15、tol 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 hep
16、atitis 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,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,
