Progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis
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DOI：
10.1016/s2210-7401(12)70018-9
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发表时间：
2012-09-01
影响因子：
2.7
通讯作者：
Jacquemin, Emmanuel
中科院分区：
文献类型：
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作者：
Jacquemin, Emmanuel
进行性家族性肝内胆汁淤积症（PFIC）是指儿童期常染色体隐性疾病的异质组，这些疾病破坏胆汁形成并表现为肝细胞来源的胆汁淤积。确切的患病率尚不清楚，但估计发病率在1/50,000到1/100,000之间。已经确定了三种类型的PFIC，并与参与胆汁形成的肝细胞运输系统基因突变有关。PFIC1和PFIC2通常出现在生命的头几个月，而PFIC3可能出现在婴儿期、儿童期甚至青年期。主要临床表现为胆汁淤积、瘙痒、黄疸。PFIC患者通常在成年前发展为纤维化和终末期肝病。血清γ -谷氨酰转移酶（GGT）活性在PFIC1和PFIC2患者中正常，但在PFIC3患者中升高。PFIC1和PFIC2都是由于编码FIC1蛋白的ATP881和编码胆汁盐输出泵（BSEP）蛋白的ABC811缺陷导致的胆汁盐分泌受损而引起的。编码多药耐药3蛋白（MDR3）的ABC84缺陷损害胆道磷脂分泌，导致PFIC3。诊断依据临床表现、肝脏超声检查、胆管造影和肝脏组织学，以及排除儿童胆汁淤积的其他原因的具体检查。MDR3和BSEP肝脏免疫染色，以及胆脂成分分析应有助于选择PFIC候选人，并提出基因分型以确诊。产前诊断可建议对已发现突变的受影响家庭进行诊断。所有患者均应开始熊去氧胆酸（UDCA）治疗，以防止肝损害。在一些PFIC1和PFIC2患者中，胆道转移也可以缓解瘙痒和减缓疾病进展。然而，大多数PFIC患者最终都是肝移植的候选者。肝肿瘤监测，特别是PFIC2患者，应从出生后第一年开始。肝细胞移植、基因治疗和特异性靶向药物治疗可能是未来的替代治疗方法。(C) 2012 Elsevier Masson SAS。版权所有。
Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP881 encoding the FIC1 protein and in ABC811 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABC84, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future. (C) 2012 Elsevier Masson SAS. All rights reserved.