进行性家族性肝内胆汁淤积症的基因分型及治疗进展

刘怡静; 周方

doi:10.12449/JCH250428

进行性家族性肝内胆汁淤积症的基因分型及治疗进展

DOI: 10.12449/JCH250428

刘怡静,
周方^, ,

郑州大学附属儿童医院（河南省儿童医院，郑州儿童医院）消化科，郑州 450053

基金项目:

河南省医学科技攻关省部共建重点计划项目 (SBGJ202002125);

河南省科技攻关计划项目 (232102311124)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘怡静负责课题设计，论文构思及撰写；周方负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
周方， zhoufang_78@126.com （ORCID： 0000-0003-0722-4253）

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出版历程
- 收稿日期: 2024-07-01
- 录用日期: 2024-07-30
- 出版日期: 2025-04-25

Advances in genotyping and treatment of progressive familial intrahepatic cholestasis

Yijing LIU,
Fang ZHOU^{,
,}

Department of Digestion，Children’s Hospital Affiliated to Zhengzhou University，Henan Children’s Hospital，Zhengzhou Children’s Hospital，Zhengzhou 450053，China

Research funding:

Key Medical Science and Technology Project of Henan Province (SBGJ202002125);

Henan Provincial Science and Technology Plan Project (232102311124)

More Information

Corresponding author: ZHOU Fang， zhoufang_78@126.com （ORCID： 0000-0003-0722-4253）

摘要

摘要: 进行性家族性肝内胆汁淤积症（PFIC）是一组罕见的常染色体隐性遗传病。近年来，随着分子生物学发展，不断有新的致病基因被发现，根据在线人类孟德尔遗传数据库，基因分型目前分为12型。PFIC主要表现为黄疸、瘙痒、生长发育迟缓及脂溶性维生素吸收不良等，一些变异型迅速进展为肝纤维化、肝硬化、肝衰竭，甚至肝癌。不同类型PFIC临床表现和治疗策略不尽相同，基因检测有助于实现早期识别及诊断。本文就PFIC基因分型、临床特征和治疗进展进行综述。
- 胆汁淤积，肝内 /
- 基因型 /
- 治疗学
Abstract: Progressive family intrahepatic cholestasis （PFIC） is a rare group of autosomal recessive disorders. In recent years， with the development of molecular biology， new pathogenic genes have been constantly identified， and PFIC is currently categorized into 12 genotypes based on the OMIM database. The main manifestations of PFIC include jaundice， pruritus， growth retardation， and malabsorption of fat-soluble vitamins， and some variants can rapidly progress to liver fibrosis， liver cirrhosis， liver failure， and even liver cancer. Different types of PFIC have different clinical manifestations and treatment strategies， and genetic testing can help to achieve early identification and diagnosis. This article reviews the latest advances in the genotyping， clinical features， and treatment of PFIC.
- Cholestasis， Intrahepatic /
- Genotype /
- Therapeutics

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表 1 PFIC基因分型及实验室特点

Table 1. Genotype and laboratory profile of the various types of progressive familial intrahepatic cholestasis

分型	基因座/基因/蛋白	GGT	DBil	TBA	AFP	ALT/AST	病理特点
PFIC-1	18q21/ATP8B1/FIC1	正常	高	高	正常	轻度升高	肝细胞及胆小管胆汁淤积，汇管区炎症，门静脉和小叶周围纤维化，小结节性肝硬化
PFIC-2	2q31/ABCB11/BSEP	正常	高	极高	高	中度升高	毛细胆管内胆汁淤积及小叶/门静脉纤维化，巨细胞炎症，严重的肝细胞坏死
PFIC-3	7q21/ABCB4/MDR3	升高	高	高	正常	轻度升高	门静脉炎症及门静脉纤维化，胆汁淤积，胆管增生
PFIC-4	9q21/TJP2/ZO-2	正常	高	高	正常或并发HCC时升高	高	胆汁淤积及小叶/门静脉纤维化，巨细胞炎症，肝细胞坏死和肝硬化
PFIC-5	12q23/NR1H4/FXR	正常	高	高	高	中度升高	胆汁淤积及小叶/门静脉纤维化，巨细胞炎症，胆管增生和肝硬化
PFIC-6	3q29/SLC51A/OSTα	升高	高	正常	未报道	中度升高	小叶结构变形，早期肝硬化伴门静脉和门静脉周围纤维化，胆汁淤积及胆管增生
PFIC-7	4q26/USP53/USP53	正常	高	高	未报道	高	肝小叶紊乱及小叶内胆汁淤积，巨细胞炎症，汇管区纤维化
PFIC-8	9q32/KIF12/KIF12	升高	高	高	高	高	胆汁淤积及胆管增生，肝纤维化及肝硬化
PFIC-9	15q15/ZFYVE19/ZFYVE19	升高	高	高	未报道	高	小结节性肝硬化、胆汁淤积伴胆管板畸形，门静脉增宽伴纤维化，胆管增生及胆管纤维化性闭塞
PFIC-10	18q21/MYO5B/Myosin Vb	正常	高	高	正常	轻或中度升高	胆汁淤积、小叶/门静脉纤维化、胆管增生伴局灶性巨细胞炎症
PFIC-11	15q24/SEMA7A/SEMA7A	正常	正常	高	未报道	高	未见报道
PFIC-12	15q26/VPS33B/VPS33B	正常	高	轻度升高	正常	高	肝细胞及小胆管胆汁淤积，巨细胞炎症

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表 2 各型PFIC临床特征、治疗及预后

Table 2. Clinical characteristics，treatment and outcome of the various types of progressive familial intrahepatic cholestasis

分型	临床特征	肝外特征	治疗	预后
PFIC-1	起病早，黄疸/瘙痒，肝脾肿大、生长迟缓，可导致肝硬化和终末期肝病	复发性胰腺炎、腹泻、感觉神经性听力损失、慢性咳嗽、甲状腺功能低下	药物：UDCA、利福平、消胆胺、IBAT抑制剂；手术：BD、肝移植	胆汁分流术对约80%的患者有效；肝移植后的患者肝外症状可持续（或恶化）
PFIC-2	起病早，黄疸/瘙痒、门静脉高压、生长迟缓，快速进展为肝硬化，并发肝癌及胆管癌风险	胆石症	药物：UDCA、利福平、消胆胺、4-PBA、IBAT抑制剂；手术：BD、肝移植	肝移植后部分患者会产生BSEP自身抗体，导致疾病复发，可能需二次肝移植
PFIC-3	婴儿晚期至青春期均可发病，慢性胆汁淤积，瘙痒较轻，生长迟缓，并发肝癌及胆管癌风险	胆石症	药物：UDCA、利福平、消胆胺、IBAT抑制剂；手术：BD、肝移植；VTX-803	预后差异大，保留MDR3表达的患者对药物治疗反应好；症状严重者，肝移植可治愈
PFIC-4	早期严重的胆汁淤积/瘙痒；进展迅速，并发肝癌风险	听力障碍、神经和呼吸系统疾病	药物：UDCA、利福平、消胆胺、IBAT抑制剂；手术：BD、肝移植	肝移植比例高，移植后暂未见复发报道
PFIC-5	新生儿期起病胆汁淤积，不依赖维生素K的凝血功能障碍，快速进展为终末期肝病		药物：UDCA、利福平、消胆胺、IBAT抑制剂、OCA；手术：肝移植	预后差，肝移植术后可出现肝脂肪变性
PFIC-6	起病早，胆汁淤积，生长迟缓、出血，早期肝纤维化和肝硬化	慢性吸收不良性腹泻及皮肤瘀斑	药物：UDCA、消胆胺、IBAT抑制剂	2020年本病首次报道，经治疗凝血功能及生长恢复正常，转氨酶、DBil和GGT仍高
PFIC7	黄疸并顽固性瘙痒，低钙血症	听力障碍	药物：利福平、UDCA、IBAT抑制剂；手术：肝移植	药物治疗反应好，1例患者难治性瘙痒，行肝移植
PFIC-8	婴儿期出现胆汁淤积，快速进展为肝纤维化和门静脉高压，进行性硬化性胆管炎	胰腺脂肪浸润	药物：UDCA、IBAT抑制剂；手术：肝移植	目前报道13例患者，11例出现肝硬化，4例进行肝移植，1例等待移植
PFIC-9	婴儿或儿童早期黄疸/瘙痒、门静脉高压、肝脾肿大	部分患儿伴有腹泻	药物：UDCA、利福平、IBAT抑制剂；手术：肝移植	目前报道10例患儿，4例进行肝移植
PFIC-10	黄疸/瘙痒，短暂、进行性或复发性的胆汁淤积，病情进展慢	暂时性腹泻	药物：UDCA、利福平、消胆胺、IBAT抑制剂；手术：BD、肝移植	预后差异大，药物及胆汁分流术均对部分患者有效，症状严重者仍需肝移植
PFIC-11	高胆汁酸血症伴有明显肝功能损害		药物：UDCA、IBAT抑制剂和谷胱甘肽	2021首次报道，仅1例患者，目前药物治疗有效，有待继续随访
PFIC-12	起病早，黄疸/瘙痒，肝脾肿大，持续或复发性胆汁淤积		药物：UDCA、消胆胺、IBAT抑制剂；手术：BD、肝移植	2019首次报道，瘙痒药物治疗效果欠佳
注：UDCA，熊去氧胆酸；IBAT，回肠胆汁酸转运体；BD，胆汁分流术；4-PBA，4-苯基丁酸；OCA，奥贝胆酸。

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