儿童药物性肝病临床特征及基因突变分析

Clinical characteristics and gene mutations of childhood drug-induced liver disease

目的探讨儿童药物性肝病（DILD）的临床特点、肝组织病理改变及基因突变。方法回顾性分析4例DILD患儿的临床资料,并复习国内外相关文献。结果 4例患儿起病前均有相关用药病史,病程5~90 d,首诊症状多样,以黄疸、尿黄、肝功能异常、肝脏肿大就诊。2例患儿行肝穿刺活检术,肝组织病理主要表现为广泛水变性,出现灶状坏死,汇管区可见炎性细胞浸润;超微病理可见大量糖原累积、胆色素颗粒沉积及淋巴细胞浸润。2例患儿及其父母行药物性肝病相关基因检测,ABCB11基因测序显示1例患儿存在杂合突变,分别在第13号外显子13311 T〉C（V444A）及第21号外显子2594 C〉T（A865V）;另1例患儿基因检测无异常。检索国内外文献,国内药物性肝病临床分型以肝细胞为主,最常见药物为抗生素,而国外为解热镇痛药;目前已发现的ABCB11基因突变超过100多种,V444A为最常见突变位点。结论儿童药物性肝病首发症状多样,起病前有药物史、肝组织病理学检查及ABCB11基因的检测有助于诊断。

Objective To investigate the clinical features, hepatic pathology, and gene mutations of the drug-induced liver disease（DILD） in children. Methods The clinical manifestations and laboratory results from four children with DILD were retrospectively analyzed. The relevant literatures were reviewed. Results Four children with DILD all had associated medication history before onset. The courses were 5-90 days. The first symptom was various in common with jaundice, yellow urine, liver function abnormality, and hepatomegaly. Liver biopsy was performed in 2 patients. The hepatic pathological manifestation mainly showed extensive water degeneration, focal necrosis, and inflammatory cells in portal area. Ultrastructural pathology showed numerous glycogen storage, bile pigment particle deposition, and lymphocyte infiltration. Gene mutation was detected in 2 patients and their parents. The DNA sequencing of the ABCB11 gene showed heterozygous mutations in the exon of No.13, 13311 TC（V444A） and No.21, 2594 CT（A865V） in one patient. Gene mutation was not detected in another patient. The literature review showed that clinical classification was mainly composed of hepatocellular type and antibiotics were the most common medicine to induce DILD in domestic children. Meanwhile, antipyretic-analgesic was the most common medicine to induce DILD in foreign children. ABCB11 gene mutation had been found more than 100 kinds. The V444 A mutation was the most common site. Conclusions The first symptoms of children with DILD are various. Medication history before onset, hepatic pathology, and detection ABCB11 gene were helpful to diagnose DILD.