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目的探讨南京地区新生儿特发性胆汁淤积症(INC)中Citrin蛋白缺陷导致的肝内胆汁淤积症(NICCD)的发病率、SLC25A13基因突变及临床特点。方法对2009年9月到2013年8月南京医科大学附属南京儿童医院收治的152例INC患儿进行SLC25A13基因突变分析。对确诊NICCD的患儿根据年龄及性别与INC患儿进行1∶2配对,比较两组之间的生化指标。计量资料组间比较经Bonferroni校正后采用Mann-Whitney U检验。结果 152例INC患儿中经SLC25A13基因突变分析确诊为NICCD21例(21/152,13.82%),5种突变类型分别为851_854del(27/42,64.29%)、IVS6+5 G→A(7/42,16.67%)、1638ins23(5/42,11.90%)、IVS11+1 G→A(2/42,4.76%)、Q259X(1/42,2.38%)。NICCD组ALT、AST、胆汁酸、白蛋白、空腹血糖、血氨、凝血酶原时间分别为(39.42±23.40)U/L、(124.85±92.65)U/L、(142.43±24.34)μmol/L、(30.66±2.70)g/L、(2.79±0.54)mmol/L、(117.57±27.88)μmol/L、(14.03±2.79)s;INC组ALT、AST、胆汁酸、白蛋白、空腹血糖、血氨、凝血酶原时间分别为(136.02±113.67)U/L、(226.12±129.26)U/L,(80.47±31.53)μmol/L、(36.87±4.96)g/L、(3.14±0.45)mmol/L、(76.43±20.80)μmol/L、(11.40±1.55)s。NICCD组ALT、AST低于INC组,差异有统计学意义(Z=-5.02,P=0.000;Z=-3.66,P=0.000);NICCD组胆汁酸高于INC组,差异有统计学意义(Z=-5.58,P=0.000);NICCD组白蛋白、空腹血糖低于INC组,差异有统计学意义(Z=-4.52,P=0.000;Z=-2.56,P=0.010);NICCD组血氨高于INC组,差异有统计学意义(Z=-4.75,P=0.000);NICCD组凝血酶原时间较INC组延长,差异有统计学意义(Z=-4.10,P=0.000)。结论 SLC25A13基因突变所致Citrin蛋白缺陷是南京地区INC的一种重要原因,其中最常见的3种突变分别为851_854del、IVS6+5 G>A和1638_1660dup23,占所有SLC25A13等位基因变异的92.86%。重视临床分析及SLC25A13基因突变检测是明确诊断NICCD的重要手段。
Objective To investigate the incidence of intrahepatic cholestasis (NICCD), SLC25A13 gene mutation and clinical features in Citrin deficiency in neonatal idiopathic cholestasis (INC) in Nanjing. Methods The SLC25A13 gene mutation was analyzed in 152 children with INC admitted to Nanjing Children’s Hospital affiliated to Nanjing Medical University from September 2009 to August 2013. Children with diagnosed NICCD were matched with 1: 2 children according to their age and sex, and biochemical indexes were compared between the two groups. Measurement data Mann-Whitney U test was used to compare Bonferroni between groups. Results 152 patients with INC were diagnosed as NICCD by mutation analysis of SLC25A13 gene in 21 cases (21 / 152,13.82%). The five types of mutations were 851_854del (27 / 42,64.29%), IVS6 + 5 G → A 42,16.67%), 1638ins23 (5/42, 11.90%), IVS11 + 1 G → A (2 / 42,4,76%), Q259X (1/42, 2.38%). The time of ALT, AST, bile acid, albumin, fasting blood glucose, blood ammonia and prothrombin in NICCD group were (39.42 ± 23.40) U / L, (124.85 ± 92.65) U / L and (142.43 ± 24.34) μmol / L , ALT, AST, bile acid, albumin, fasting blood glucose, serum creatinine and total cholesterol in the rats in the INC group were significantly higher than those in the control group (30.66 ± 2.70) g / L, (2.79 ± 0.54) mmol / L, (117.57 ± 27.88) Blood ammonia and prothrombin time were (136.02 ± 113.67) U / L, (226.12 ± 129.26) U / L, (80.47 ± 31.53) μmol / L and 36.87 ± 4.96 g / L respectively. mmol / L, (76.43 ± 20.80) μmol / L, (11.40 ± 1.55) s. NICCD group ALT, AST lower than the INC group, the difference was statistically significant (Z = -5.02, P = 0.000; Z = -3.66, P = 0.000); NICCD group bile acid higher than the INC group, the difference was statistically significant Z = -5.58, P = 0.000). The level of albumin and fasting blood glucose in NICCD group was lower than that in INC group (Z = -4.52, P = 0.000; Z = -2.56, P = 0.010) (Z = -4.75, P = 0.000). The prothrombin time in NICCD group was longer than that in INC group, the difference was statistically significant (Z = -4.10, P = 0.000). Conclusions Citrin deficiency caused by SLC25A13 gene mutation is an important reason for INC in Nanjing. The most common three mutations are 851_854del, IVS6 + 5 G> A and 1638_1660dup23, accounting for 92.86% of all SLC25A13 alleles. Emphasis on clinical analysis and SLC25A13 gene mutation detection is an important means to diagnose NICCD.