背景:ABCB4基因相关胆汁淤积性肝病具有广泛的临床和遗传变异。基因型与临床表型之间的相关性尚不清楚。回顾性分析23例ABCB4基因相关性胆汁淤积性肝病患者的临床及病理特点。下一代测序用于鉴定遗传原因。
结果:纳入的23例患者(15名儿童和8名成人)被诊断为进行性家族性肝内胆汁淤积3型(PFIC3),药物性肝损伤(DILI),肝硬化胆汁淤积,肝硬化,轻度肝纤维化.19例患者接受肝脏病理检查,表现出纤维化,小胆管增生,CK7(+),Cu(+),胆管缺失,和肝硬化。鉴定了30种ABCB4变体,包括18种新颖的变体。
结论:ABCB4基因相关胆汁淤积性肝病具有广泛的临床和遗传变异。双等位基因ABCB4突变携带者倾向于严重的PFIC3,主要发生在儿童中;而ABCB4非双等位基因变异可导致较温和的ICP,LACP,DILI或重叠,主要是成年人。因此,ABCB4基因型与表型有特定的相关性,但也有例外。非双等位基因无效突变可导致严重的疾病。这种遗传表型的潜在机制需要进一步研究。
BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes.
RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants.
CONCLUSIONS: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.