Keitel Verena, Vogt Christoph, Häussinger Dieter, Kubitz Ralf
Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Gastroenterology. 2006 Aug;131(2):624-9. doi: 10.1053/j.gastro.2006.05.003.
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder that usually develops in the third trimester of pregnancy and persists until delivery. The cause of ICP remains elusive, but there is evidence that mutations in the canalicular ABC transporter phospholipid flippase (MDR3) and in the bile salt export pump (BSEP) can predispose for the development of ICP. MDR3 and BSEP were investigated by gene sequencing and immunofluorescence microscopy in a patient with severe ICP of early onset. ICP was diagnosed in a patient in the first trimester of pregnancy with severe pruritus, elevated levels of bile salts, and 48-fold elevation of transaminase levels. A liver biopsy specimen showed diminished canalicular expression of the bile salt export pump BSEP, while the expression and localization of the phospholipid flippase MDR3 was normal. Gene sequencing revealed a homozygous MDR3 gene mutation (S320F). The patient was also homozygous for the common BSEP polymorphism V444A. Treatment with ursodeoxycholate normalized transaminase levels but could not prevent further elevation of bile salt levels and preterm delivery. The combined homozygous alterations of the canalicular transporters may explain the early onset and severity of ICP in this patient. The common BSEP polymorphism V444A accounts for the reduced canalicular BSEP expression. Reduced bile salt secretion through BSEP may explain the persistence of elevated bile salt levels and incomplete efficacy of ursodeoxycholate treatment.
妊娠肝内胆汁淤积症（ICP）是一种胆汁淤积性疾病，通常在妊娠晚期发病并持续至分娩。ICP的病因尚不清楚，但有证据表明，胆小管ABC转运体磷脂翻转酶（MDR3）和胆盐输出泵（BSEP）的突变可能易导致ICP的发生。对一名早发型重度ICP患者进行了基因测序和免疫荧光显微镜检查，以研究MDR3和BSEP。一名妊娠早期患者出现严重瘙痒、胆盐水平升高以及转氨酶水平升高48倍，被诊断为ICP。肝活检标本显示胆盐输出泵BSEP的胆小管表达减少，而磷脂翻转酶MDR3的表达和定位正常。基因测序显示存在纯合子MDR3基因突变（S320F）。该患者对于常见的BSEP多态性V444A也是纯合子。用熊去氧胆酸治疗使转氨酶水平恢复正常，但无法阻止胆盐水平进一步升高和早产。胆小管转运体的联合纯合子改变可能解释了该患者ICP的早发和严重程度。常见的BSEP多态性V444A导致胆小管BSEP表达降低。通过BSEP的胆盐分泌减少可能解释了胆盐水平持续升高以及熊去氧胆酸治疗效果不完全的原因。
