先天性非溶血性高间接胆红素血症19例临床分析

Clinical analysis of 19 cases of congenital non-hemolytic unconjugated hyperbilirubinemia

目的探讨湖南张家界地区新生儿期起病的先天性非溶血性高间接胆红素血症患儿的临床特征及转归预后。方法收集张家界市人民医院新生儿科收治的19例足月先天性非溶血性高间接胆红素患儿住院期间的临床资料,对其临床表现、外周血检测特点、基因学诊断、原发病预后及随访结果进行总结分析。结果19例先天性非溶血性高间接胆红素血症患儿最终通过全外显子测序诊断,发现6个编码胆红素-尿苷二磷酸葡萄糖醛酸转移酶(UGT1A1)的基因突变位点,突变类型均为错义突变,其中单纯纯合突变10例(52.6%)、单纯杂合突变5例(26.3%)及复合杂合突变4例(21.1%),汉族、土家族分别达2例及17例。临床表现以皮肤重度黄染最常见,14例患儿出现重度及以上高胆红素血症(>342μmol/L)。7例患儿同时接受外周动静脉同步换血及间歇性双面蓝光疗法,接受换血疗法中位时间为生后7.2 d(四分位数间距:5.9,7.3 d),接受光疗时间平均(34.7±17.0)h。12例患儿行间歇性双面蓝光疗法,接受光疗时间平均(38.3±12.7)h。治疗后血清间接胆红素水平均较治疗前下降,治疗过程中3例患儿出现胆汁淤积症,其中1例病情反复。随访发现19例患儿基本生长发育均尚可,短期内出现典型胆红素脑病1例,2月龄后症状逐渐好转。结论本组先天性非溶血性高间接胆红素血症病例血清胆红素值大部分超出重度高胆红素血症水平,且发病主要与c.211G>A、c.1091C>T、c.1318A>G、c.1348C>T、c.686C>A、c.1456T>G突变相关,以c.211G>A单纯纯合突变多见;通过外周动静脉同步换血及间歇性双面蓝光疗法可缓解先天性非溶血性高间接胆红素血症患儿原发病症状,但在治疗及随访过程中仍需警惕新生儿胆红素脑病及胆汁淤积性肝炎等并发症。

Objective To investigate the clinical characteristics and prognosis of regression in children with congenital non-hemolytic unconjugated hyperbilirubinemia starting in the neonatal period in Zhangjiajie,Hunan Province.Methods Clinical data of 19 full-term congenital non-hemolytic unconjugated hyperbilirubinemiac children admitted to the neonatal unit of Zhangjiajie People's Hospital were collected during their hospitalization,and their clinical manifestations,peripheral blood test characteristics,genetic diagnosis,prognosis of primary disease and follow-up results were summarized and analyzed.Results Nineteen children with congenital nonhemolytic unconjugated hyperbilirubinemia were finally diagnosed by whole-exome sequencing,and six mutation loci encoding bilirubin-uridine diphosphate glucuronosyltransferase(UGT1A1)were identified,and all mutation types were missense mutations,including 10 pure mutations alone(52.6%),5 pure heterozygous mutations(26.3%)and 4 compound heterozygous mutations(21.1%),with 2 and 17 cases in Han and Tu families,respectively.The most common clinical manifestation was severe skin jaundice,and 14 children had severe or higher hyperbilirubinemia(>342μmol/L)7 children received simultaneous peripheral arteriovenous blood exchange and intermittent double-sided blue light therapy,and the median time of receiving blood exchange therapy was 7.2 d postnatally(Interquartile spacing:5.9,7.3 d),and the average time of receiving light therapy was(34.7±17.0)h.12 children received intermittent double-sided blue light therapy.After treatment,the serum indirect bilirubin level decreased compared to the previous level.At follow-up,the basic growth and development of all 19 children were found to be fair,with one case of typical bilirubin encephalopathy in the short term,with gradual improvement of symptoms after 2 months of age.Conclusion In our group,the majority of congenital non-hemolytic unconjugated hyperbilirubinemia cases had serum bilirubin values exceeding the level of severe hyperbilirubinemia,and the pathogenesis was mainly associated with c.211G>A,c.1091C>T,c.1318A>G,c.1348C>T,c.686C>A,and c.1456T>G mutations,with c.211G>A simple pure mutations the most common;the primary symptoms of congenital non-hemolytic unconjugated hyperbilirubinemia were relieved by simultaneous peripheral arteriovenous blood exchange and two-sided blue light therapy.Simultaneous peripheral arteriovenous blood exchange and intermittent two-sided blue light therapy can alleviate the primary symptoms in children with congenital nonhemolytic unconjugated hyperbilirubinemia,but it is still necessary to be alert for complications such as neonatal bilirubin encephalopathy and cholestatic hepatitis during treatment and follow-up.