探讨ABCB4基因突变合并巨细胞病毒(CMV)感染致婴儿胆汁淤积症(IC)患儿的临床特征、基因检测结果和诊治方案。

选择2019年8月3日，于中山大学附属第七医院就诊并确诊为ABCB4基因突变合并CMV感染致IC的1例婴儿(女性，生后9个月)为研究对象。回顾性分析其临床病例资料，包括临床特征、实验室检查结果及基因检测结果。同时，检索国内外数据库中ABCB4基因突变所致IC患儿的相关文献，并进行文献复习。本研究遵循的程序符合2013年新修订的《世界医学协会赫尔辛基宣言》要求。

本例IC患儿在本院诊治结果如下。①病史采集：系G₂P₂，足月顺产，外观无异常，否认新生儿黄疸病史，生后2个月龄时出现皮肤及巩膜呈暗绿色，伴反复呕奶，当地医院治疗并诊断为胆汁淤积性肝病、CMV感染和泌尿系统感染，抗病毒治疗2周后好转出院。出院时，其血清总胆汁酸(sTBA)为152.8 μmol/L，CMV-DNA<4×10² copies/mL，口服熊去氧胆酸胶囊10 mg/(kg·d)治疗后，皮肤暗绿色逐渐消退，大、小便正常。出院后定期监测肝功能，sTBA、γ-谷氨酰转肽酶(GGT)仍然较正常值增高。②实验室检查：血清CMV免疫球蛋白(Ig)G抗体呈阳性、CMV IgM抗体呈阴性，CMV-DNA<55×10² copies/mL。基因检测结果：患儿及其父亲均携带ABCB4基因杂合变异。治疗结果：经口服熊去氧胆酸胶囊10 mg/(kg·d)及谷胱甘肽片0.1 g/次× 3次/d治疗后，对患儿定期复查sTBA、GGT。随访到18个月龄时，其各项指标逐渐恢复正常范围。③文献复习结果：共计检索到8篇国内外报道的因ABCB4基因突变引起IC相关文献，纳入14例IC患儿，均被诊断为进行性家族性肝内胆汁淤积3型(PFIC3)，伴肝大，sTBA、GGT水平升高等。14例IC患儿中，共检测到ABCB4基因突变位点20个。其中，9例IC患儿接受熊去氧胆酸治疗，7例随访结果显示临床症状及实验室检查指标有所好转。

携带ABCB4基因突变，可引起IC。对于sTBA升高、肝酶异常的病因不明确、治疗效果不佳IC患儿，建议完善基因检测进一步排查ABCB4基因突变所致胆汁淤积症。

To explore clinical features, gene detection results, diagnosis and treatment of infant cholestasis (IC) caused by ABCB4 gene mutation and cytomegalovirus (CMV) infection.

A 9-month-old girl was admitted to the outpatient department of the Seventh Affiliated Hospital of Sun Yat-Sen University due to the increase of serum total bile acid (sTBA) for 9 months with no yellow skin, rash, liver and spleen enlargement. The clinical data, including clinical features, outpatient examination results, laboratory findings and gene detection, were retrospectively analyzed. Meanwhile, the relevant literature of children with IC caused by ABCB4 gene mutation in home and abroad databases were searched, and the literatures were reviewed. The procedure followed in the whole study were in accordance with World Medical Association Declaration of Helsinki revised in 2013.

①The girl visited our outpatient department at 9 months old, and the level of sTBA was 410.1 μmol/L. She was G₂P₂, born by delivery at full term, had no abnormal appearance and had no history of " neonatal jaundice" . Two months after birth, she developed dark green skin and sclera with repeated vomiting of milk. She was admitted to the local children′s hospital and was diagnosed as " cholestatic liver disease, cytomegalovirus infection and urinary tract infection" . She was discharged after 2 weeks of treatment with ganciclovir. The bile acid level was 152.8 μmol/L and CMV-DNA was less than 4×10² copies/mL. After discharge, ursodeoxycholic acid capsule, 10 mg/(kg·d), was taken orally. Her dark green color of skin gradually faded and she did not defecate in the shape of clay soil. Her liver function was monitored and sTBA concentration and gamma-glutamyl transpeptidase (GGT) level still higher than normal. ②Laboratory test results in our hospital were as follows. Serum CMV immunoglobulin (Ig) G antibody was positive, CMV IgM antibody was negative, CMV-DNA was less than 55×10² copies/mL and the hepatobiliary ultrasound was normal. Exome sequencing showed that she and her father carried ABCB4 gene variation. She was given oral treatment with ursodeoxycholic acid capsule 10 mg/(kg·d) and glutathione tablet 0.1 g, 3 times per day. sTBA and liver enzymes gradually decreased to the normal range after 18 month of following-up. ③Literature review results were as follows. A total of 8 domestic and foreign literatures about IC caused by ABCB4 gene mutation were retrieved, involving 14 children, who were all diagnosed with progressive familial IC type 3 (PFIC3), accompanied by liver enlargement, elevated sTBA and GGT levels.A total of 20 mutation sites of ABCB4 gene were detected in these children, 9 cases received ursodeoxycholic acid, and 7 cases showed improvement in clinical symptoms and results of laboratory test.

Children with ABCB4 gene mutation complicated with CMV detection can cause IC. As to children with persistent elevated sTBA, abnormal liver enzymes, unclear etiology and poor therapeutic effect, it is recommended to conduct the gene detection to further investigate IC caused by ABCB4 gene abnormality.