1、“特發性特發性”新生兒肝炎新生兒肝炎 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 prognosis 12 with normal GGT, All poor prognosisMaggiore G, et al. J Pediatr, 1987;11

2、2:251-252.第1頁/共37頁Kings病例入選標準病例入選標準 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第2頁/共37頁Wang JS, Eur J Pediatr, 2006, in press第3頁/共37頁病

3、例排除標準病例排除標準 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.第4頁/共37頁Basic info

4、rmation 128 cases elected, 110 biopsyed 6 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例預后不良(P=0.001) 峰值GT 100U/L進行分組 100U/L組10例，6例預后不良 100U/L組28例，2例預后不良(P=0.002) 血清GGT水平和預后的有關（和CMV狀態無關）王中林. 肝臟

5、 2005，(4)第9頁/共37頁進行性家族性肝內郁膽（進行性家族性肝內郁膽（PFICPFIC） 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第10頁/共37頁第11頁/共37頁FIC1 deficiency BRIC 基因定位18q21-22 Houwe

6、n RH, 1994, Nat Genet 8:380 PFIC (Byler disease)基因定位18q21-22 Carlton VE, 1995, 4:1049-1053 PFIC遺傳異質性，PFIC1 ATP8B1基因，編碼的產物FIC1 Bull LN, Nat Genet 1998, 18:219第12頁/共37頁FIC1 deficiency (續續) Greenland familial cholestasis, Asp554Asn Klomp LW, Hepatology, 2000,32:1337 各地的散發性病例 無家族史、父母非近親婚配 歐洲、日本、中國臺灣 新認識

7、 PFIC1和BRIC 1有同一基因引起 PFIC多見缺失、移位、無義突變 BRIC多見錯義突變 PFIC1和BRIC 1可表現為一連續過程 共同的臨床特征第13頁/共37頁Low GGT in cholestasisLow GGT expressionDefect of bile salt exportation第14頁/共37頁BSEP deficiency 1997年，低GGT PFIC的第二個基因（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 Strau

8、tnieks SS. Nat Genet. 20,233. 2004 年，BRIC 2由ABCB11突變 PFIC多見缺失、移位、無義突變, BRIC多見錯義突變 van Mil SWC, Gastroenterology, 127,379. PFIC 2 見于歐洲、日本、 中國等世界各地第15頁/共37頁Case 2 20061388 GA, A167I 第16頁/共37頁Case 3 CAG TAGExon 18 C2230T Q702Stop 第17頁/共37頁 Case 5 Intron 22 (+3) Exon 7 T A 562 GT G188W第18頁/共37頁Case 5 In

9、tron 22 (+3) 緊鄰剪切位點(ACCT) T to A Hum AAGATTACCTG Mus AAGATTACCTG Dog AAGATTACCTG Cow TAGATTACCTG Case AAGATAACCTG第19頁/共37頁Case 7 Intron 6 T+63T/G (167) 第20頁/共37頁Low GGT in cholestasisDefect of bile salt exportationDefect of bile salt synthesis第21頁/共37頁Bile acid synthetic defect 16 enzymes catalyze 1

10、7 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

11、,102,1690第22頁/共37頁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 neonatal PICSchwar

12、z 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第23頁/共37頁對臨床的意義對臨床的意義 將PFIC和BRIC區分出不同的類型 Diarrhea, Pancreatitis （PFIC1) 膽石癥 （PFIC2) 將PFIC和BRIC有機的聯系在一起 疾病的兩極，表型可轉換 van Ooteghem NA, J Hepat

13、ol 2002,36,439 預后判斷 More progressive in BSEP Malignancy in BSEP Growth retardation in FIC1第24頁/共37頁對臨床的意義對臨床的意義 Histology PFIC1：Cholestasis with nonspecific hepatitis, Low expression of GGT at canalicular PFIC2：Neonatal hepatitis （multinuclear giant cell transformation) Bile acid synthetic defect: G

14、iant 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第25頁/共37頁對臨床的意義對臨床的意義 Treatment Exogenous bile acid administration Cure for some bile acid synthetic defect Transplatation cure the disease in BSEP Outside liver

15、symptoms continue(FIC1) Partial bile diversion D482G or E297G respond well in BSEP第26頁/共37頁“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

16、 of 873 days There were no patient deaths第27頁/共37頁根據入院時GGT分組，組織學表現有區別第28頁/共37頁第29頁/共37頁Wang JS, Eur J Pediatr, 2006, in press第30頁/共37頁GGT 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 an

17、d disease resolved by day 151.Typical biochemistry dynamic profile in “transit”patients第31頁/共37頁Biochemistry 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 bili

18、rubin & AST levels fell.第32頁/共37頁Children 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 neonata