143例Citrin缺陷导致新生儿肝内胆汁淤积症患儿的血浆氨基酸谱分析

Analysis of plasma amino acid profile in 143 neonates with neonatal intrahepatic cholestasis caused by Citrin deficiency

目的探讨Citrin缺陷导致的新生儿肝内胆汁淤积症(NICCD)患儿血浆氨基酸谱特点及氨基酸谱与基因型的相关性。方法选取2004-2019年在该院确诊的NICCD患儿143例为NICCD组,56例健康新生儿为对照组,49例不明原因肝内胆汁淤积症(INH)患儿为INH组,对3组的各氨基酸水平进行比较,并采用受试者工作特征(ROC)曲线分析部分氨基酸的诊断价值。将NICCD患儿分为<6个月组、6个月至1岁组,比较2组瓜氨酸、蛋氨酸、组氨酸、苏氨酸、亮氨酸、异亮氨酸水平。将NICCD患儿按SLC25A13基因突变类型分为复合杂合突变组与纯合突变组并进行天冬氨酸、谷氨酸水平比较。结果与对照组、INH组比较,NICCD患儿天冬酰胺、组氨酸、瓜氨酸、蛋氨酸、苏氨酸、酪氨酸、天冬氨酸、鸟氨酸、赖氨酸、精氨酸、丝氨酸水平升高,谷氨酰胺和色氨酸水平降低,差异均有统计学意义(P<0.05)。与<6个月的NICCD患儿比较,6个月至1岁的NICCD患儿瓜氨酸、苏氨酸水平降低,蛋氨酸水平升高(P<0.05)。瓜氨酸、蛋氨酸、苏氨酸、酪氨酸用于NICCD诊断的ROC曲线下面积(AUC)分别为0.986(95%CI 0.974~0.998)、0.850(95%CI 0.786~0.915)、0.899(95%CI 0.849~0.949)、0.700(95%CI 0.620~0.781)。瓜氨酸/丝氨酸、瓜氨酸/(亮氨酸+异亮氨酸)、苏氨酸/丝氨酸用于NICCD诊断的AUC分别为0.968(95%CI 0.946~0.991)、0.984(95%CI 0.970~0.998)、0.896(95%CI 0.833~0.960)。NICCD患儿纯合突变组的天冬氨酸、谷氨酸水平比复合杂合突变组高(P<0.05)。结论血浆氨基酸谱分析是筛查和诊断NICCD的一种灵敏、快速的方法,较为灵敏的诊断指标为瓜氨酸、瓜氨酸/(亮氨酸+异亮氨酸)。

Objective To investigate the characteristics of plasma amino acid profile and the correlation between amino acid profile and genotype in children with neonatal intrahepatic cholestasis(NICCD)caused by Citrin deficiency.Methods 143 children with NICCD diagnosed in our hospital from 2004 to 2019 were enrolled as NICCD group,56 healthy newborns were selected as control group,and 49 children with unexplained intrahepatic cholestasis(INH)children were enrolled as INH group.The amino acid levels of the three groups were compared,and receiver operating characteristic(ROC)curves were used to analyze the diagnostic value of some amino acids.Children with NICCCD were divided into<6 months group and 6 months to 1 year old group.The levels of citrulline,methionine,histidine,threonine,leucine and isoleucine were compared between the two groups.Children with NICCCD were divided into compound heterozygous mutation group and homozygous mutation group according to the type of SLC25A13 gene mutation,and the levels of aspartate and glutamate were compared.Results Compared with normal control group and INH group,the levels of asparagine,histidine,citrulline,methionine,threonine,tyrosine,aspartic acid,ornithine,lysine,arginine and serine in NICCD children increased,and the levels of glutamine and tryptophan decreased(P<0.05).Compared with children with NICCD less than 6 months old,the levels of citrulline and threonine in children with NICCD from 6 months to 1 year were decreased,and the level of methionine was increased(P<0.05).The area under ROC curve(AUC)of citrulline,methionine,threonine and tyrosine for the diagnosis of NICCD were 0.986(95%CI 0.974-0.998),0.850(95%CI 0.786-0.915),0.899(95%CI 0.849-0.949)and 0.700(95%CI 0.620-0.781),respectively.The AUC of citrulline/serine,citrulline/(leucine+isoleucine)and threonine/serine for the diagnosis of NICCD were 0.968(95%CI 0.946-0.991),0.984(95%CI 0.970-0.998)and 0.896(95%CI 0.833-0.960),respectively.The levels of aspartate and glutamate in the homozygous mutation group were higher than those in the compound heterozygous mutation group(P<0.05).Conclusion Plasma amino acid profile analysis is a sensitive and rapid method for screening and diagnosing NICCCD.The more sensitive diagnostic indicators are citrulline,citrulline/(leucine+isoleucine).