Zhou Kejun, Wang Jun, Xie Guoxiang, Zhou Ying, Yan Weihui, Pan Weihua, Che Yanran, Zhang Ting, Wong Linda, Kwee Sandi, Xiao Yongtao, Wen Jie, Cai Wei, Jia Wei
Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) , Shanghai 200092, China.
Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research , Shanghai 200092, China.
J Proteome Res. 2015 Nov 6;14(11):4844-50. doi: 10.1021/acs.jproteome.5b00676. Epub 2015 Oct 16.
Biliary atresia (BA) is a severe chronic cholestasis disorder of infants that leads to death if not treated on time. Neonatal hepatitis syndrome (NHS) is another leading cause of neonatal cholestasis confounding the diagnosis of BA. Recent studies indicate that altered bile acid metabolism is closely associated with liver injury and cholestasis. In this study, we systematically measured the bile acid metabolome in plasma of BA, NHS, and healthy controls. Liver bile acids were also measured using biopsy samples from 48 BA and 16 NHS infants undergoing operative cholangiography as well as 5 normal adjacent nontumor liver tissues taken from hepatoblastoma patients as controls. Both BA and NHS samples had significantly elevated bile acid levels in plasma compared to normal controls. BA patients showed a distinct bile acid profile characterized by the higher taurochenodeoxycholic acid (TCDCA) level and lower chenodeoxycholic acid (CDCA) level than those in NHS patients. The ratio of TCDCA to CDCA in plasma was significantly higher in BA compared to healthy infants (p < 0.001) or NHS (p < 0.001). The area under receiver operating characteristic curve for TCDCA/CDCA to differentiate BA from NHS was 0.923 (95% CI: 0.862-0.984). These findings were supported by significantly altered expression levels of bile acid transporters and nuclear receptors in liver including farnesoid X receptor (FXR), small heterodimer partner (SHP), bile salt export pump (BSEP), and multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken together, the plasma bile acid profiles are distinct in BA, NHS, and normal infants, as characterized by the ratio of TCDCA/CDCA differentially distributed among the three groups of infants.
胆道闭锁（BA）是一种严重的婴儿慢性胆汁淤积性疾病，若不及时治疗会导致死亡。新生儿肝炎综合征（NHS）是导致新生儿胆汁淤积、混淆BA诊断的另一个主要原因。最近的研究表明，胆汁酸代谢改变与肝损伤和胆汁淤积密切相关。在本研究中，我们系统地测量了BA、NHS患儿以及健康对照者血浆中的胆汁酸代谢组。还使用了48例接受手术胆管造影的BA患儿和16例NHS患儿的活检样本以及取自肝母细胞瘤患者的5块正常相邻非肿瘤肝组织作为对照，测量了肝脏胆汁酸。与正常对照相比，BA和NHS样本的血浆胆汁酸水平均显著升高。BA患者表现出独特的胆汁酸谱，其特征是牛磺鹅去氧胆酸（TCDCA）水平高于NHS患者，鹅去氧胆酸（CDCA）水平低于NHS患者。与健康婴儿（p < 0.001）或NHS（p < 0.001）相比，BA患者血浆中TCDCA与CDCA的比值显著更高。TCDCA/CDCA区分BA与NHS的受试者工作特征曲线下面积为0.923（95%CI：0.862 - 0.984）。与NHS相比，BA肝脏中胆汁酸转运体和核受体包括法尼醇X受体（FXR）、小异二聚体伴侣（SHP）、胆盐输出泵（BSEP）和多药耐药蛋白3（MDR3）的表达水平显著改变，支持了这些发现。综上所述，BA、NHS和正常婴儿血浆中的胆汁酸谱不同，其特征是TCDCA/CDCA比值在三组婴儿中分布不同。
