进行性家族性肝内胆汁淤积症1型的遗传与临床谱：新型ATP8B1变异及基因型-表型相关性

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中文摘要

背景： 进行性家族性肝内胆汁淤积症1型（PFIC1）是一种由ATP8B1变异引起的罕见遗传性疾病。本研究旨在描述PFIC1的临床与遗传谱，并探讨受累个体的基因型-表型相关性。方法：收集并分析了15例新发现的PFIC1患者的临床表现和实验室检查结果，以及从PubMed和CNKI数据库检索到的70例既往报道病例的数据。结果：共鉴定出10个新型致病性或可能致病性ATP8B1变异。临床表现包括胆汁淤积性黄疸、瘙痒、肝肿大、腹泻、耳聋和胰腺炎，并伴有血清转氨酶、总/直接胆红素和总胆汁酸水平升高，而γ-谷氨酰转肽酶（GGT）水平正常或偏低。大多数PFIC1患者（71.2%，42/59）对口服熊去氧胆酸（UDCA）反应不足。在接受肝移植（LT）的患者中，术后严重并发症常见，包括肝脂肪变性（93.3%，14/15）和难治性腹泻（86.7%，13/15）。相比之下，肝移植联合手术胆道分流（SBD）将这两种并发症的发生率均降至44.4%（4/9）。末次随访时，64.7%（44/68）的病例出现不良临床结局。与携带非双等位基因无效ATP8B1变异的个体相比，携带双等位基因无效变异的个体发病年龄更早、对UDCA的应答率更低，且无肝移植生存期缩短。结论：本研究描述了15例携带10个新型ATP8B1变异的PFIC1新病例。PFIC1涉及多系统表现，其中GGT正常的胆汁淤积性肝炎是其典型特征。UDCA的疗效仍然有限，单纯肝移植与大量术后并发症相关，而肝移植联合SBD似乎可降低并发症发生率。携带双等位基因无效ATP8B1变异的个体表现出更早的疾病发病以及更差的治疗和临床结局。

英文摘要

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a rare genetic disorder caused by variants in ATP8B1. The aim of this study was to characterize the clinical and genetic spectrum of PFIC1 and to investigate genotype-phenotype correlations in affected individuals. Clinical manifestations and laboratory findings from 15 newly identified individuals with PFIC1, together with data from 70 previously reported cases retrieved from the PubMed and CNKI databases, were collected and analyzed. A total of 10 novel pathogenic or likely pathogenic ATP8B1 variants were identified. Clinical manifestations included cholestatic jaundice, pruritus, hepatomegaly, diarrhea, deafness, and pancreatitis, accompanied by elevated serum transaminase, total/direct bilirubin, and total bile acid levels, with normal or low gamma-glutamyl transpeptidase (GGT) levels. Most patients with PFIC1 (71.2%, 42/59) showed an insufficient response to oral ursodeoxycholic acid (UDCA). Among patients who underwent liver transplantation (LT), severe postoperative complications, including hepatic steatosis (93.3%, 14/15) and intractable diarrhea (86.7%, 13/15), were common. In contrast, LT combined with surgical biliary diversion (SBD) reduced the incidence of these complications to 44.4% (4/9) for both outcomes. At the last follow-up, unfavorable clinical outcomes were observed in 64.7% (44/68) of cases. Compared with individuals carrying non-biallelic null ATP8B1 variants, those with biallelic null variants had an earlier age at onset, a lower response rate to UDCA, and reduced LT-free survival. Conclusion: This study described 15 new cases of PFIC1 carrying 10 novel ATP8B1 variants. PFIC1 involved multisystem manifestations, with normal-GGT cholestatic hepatitis representing a characteristic feature. The therapeutic efficacy of UDCA remained limited, and LT alone was associated with substantial postoperative complications, whereas combined LT and SBD appeared to reduce complication rates. Individuals with biallelic null ATP8B1 variants demonstrated earlier disease onset and poorer therapeutic and clinical outcomes.