ATP结合盒亚家族B成员4（ABCB4）基因突变相关性肝硬化合并胆囊结石1例报告

刘文迪; 王芃; 胡和平; 周华邦

doi:10.12449/JCH240324

ATP结合盒亚家族B成员4（ABCB4）基因突变相关性肝硬化合并胆囊结石1例报告

DOI: 10.12449/JCH240324

海军军医大学东方肝胆外科医院肝胆内科，上海 200438

伦理学声明：本例报告已获得患者及家属知情同意。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘文迪、王芃负责收集数据，资料分析，撰写文章；胡和平、周华邦负责课题设计，拟定写作思路，修改文章并最后定稿。

详细信息

通信作者:
周华邦， zhouhb513@126.com （ORCID： 0000-0002-0301-4876）

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出版历程
- 收稿日期: 2023-05-09
- 录用日期: 2023-06-20
- 出版日期: 2024-03-20

ABCB4 gene mutation-associated liver cirrhosis with gallstones： A case report

Department of Hepatobiliary Medicine，Eastern Hepatobiliary Surgery Hospital，Navy Medical University，Shanghai 200438，China

More Information

Corresponding author: ZHOU Huabang， zhouhb513@126.com （ORCID： 0000-0002-0301-4876）

摘要

摘要: ATP结合盒亚家族B成员4（ABCB4）基因突变疾病谱涉及进行性家族性肝内胆汁淤积3型、胆石症、妊娠期肝内胆汁淤积症、门静脉高压、肝硬化，甚至原发性肝脏、胆道恶性肿瘤等多种疾病。本院肝胆内科收治1例青年男性患者，入院初步诊断为胆囊结石，计划腹腔镜胆囊切除术，术前检查发现该患者肝功能异常、肝硬化、脾大、食管静脉轻度曲张，后进一步行二代测序明确诊断为ABCB4基因突变相关性肝硬化合并胆囊结石，给予熊去氧胆酸胶囊利胆治疗后，肝功能逐渐恢复正常。
- ABCB4基因 /
- 突变 /
- 多药耐药相关蛋白质类 /
- 肝硬化 /
- 胆石
Abstract: The disease spectrum of ABCB4 gene mutation involves various diseases such as progressive familial intrahepatic cholestasis type 3 （PFIC3）， gallstone disease， intrahepatic cholestasis of pregnancy， portal hypertension， liver cirrhosis， and even primary hepatic and biliary malignancies. A young male patient was admitted to Department of Hepatobiliary Medicine， Eastern Hepatobiliary Surgery Hospital， and was initially diagnosed with liver cirrhosis and gallstones， and he was planned to receive laparoscopic cholecystectomy. Preoperative examination showed abnormal liver function， liver cirrhosis， splenomegaly， and mild esophageal varices， and next-generation sequencing was performed to make a confirmed diagnosis of ABCB4 gene mutation-associated liver cirrhosis with gallstones. The liver function of the patient gradually returned to normal after cholagogic treatment with ursodeoxycholic acid capsules.
- ABCB4 Gene /
- Mutation /
- Multidrug Resistance-Associated Proteins /
- Liver Cirrhosis /
- Gallstones

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图 1 肝脏增强MRI及胃镜结果

注： a，增强MRI的T₂WI示肝硬化、脾大、胆囊炎；b，增强MRI的延迟期示肝胃间隙侧支血管形成；c，MRCP示肝周少量积液及胆囊颈部结石；d，胃镜示食管下段静脉轻度曲张。

Figure 1. Liver enhanced MRI and gastroscopy

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图 2 患者及其父母等全外显子基因测序结果

注：患者ABCB4基因发现2个杂合变异，一处为NM_000443.3：c.602C>T（p.Thr201Met），即编码区第602位碱基由C突变为 T，突变导致编码蛋白的第201位氨基酸由苏氨酸突变成甲硫氨酸，此处突变来源于患者的父亲；另一处为NM_000443.3：c.3121T>C（p.Phe1041Leu），即编码区第3121位碱基由T突变为C，突变导致编码蛋白的第1041位氨基酸由苯丙氨酸突变成亮氨酸，此处突变来源于患者的母亲。患者的姐姐亦检测到来源于父亲的突变：NM_000443.3：c.602C>T（p.Thr201Met）。

Figure 2. Sequence diagram of the whole Exon gene of the patient and his parents

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表 1 患者基因突变信息及可能出现的临床疾病表型

Table 1. Genetic mutation information of patients and possible clinical disease phenotypes

基因	染色体	核苷酸/氨基酸变化	基因亚区	合子状态	疾病/表型	遗传方式
ABCB4 （NM_000443.3）	Chr7：87081045	c.602C>T p.Thr201Met	Exon7	杂合	ICP3 PFIC3 LPAC	AR、AD AR AR、AD
ABCB4 （NM_000443.3）	Chr7：87037511	c.3121T>C p.Phe1041Leu	Exon25	杂合	ICP3 PFIC3 LPAC	AR、AD AR AR、AD
注：AR，常染色体阴性；AD，常染色体显性。

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参考文献(21)

[1]	STICOVA E, JIRSA M. ABCB4 disease: Many faces of one gene deficiency[J]. Ann Hepatol, 2020, 19( 2): 126- 133. DOI: 10.1016/j.aohep.2019.09.010.
[2]	AVENA A, PUGGELLI S, MORRIS M, et al. ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed[J]. Dig Liver Dis, 2021, 53( 3): 329- 344. DOI: 10.1016/j.dld.2020.12.003.
[3]	STICOVA E, JIRSA M, PAWŁOWSKA J. New insights in genetic cholestasis: From molecular mechanisms to clinical implications[J]. Can J Gastroenterol Hepatol, 2018, 2018: 2313675. DOI: 10.1155/2018/2313675.
[4]	STÄTTERMAYER AF, HALILBASIC E, WRBA F, et al. Variants in ABCB4(MDR3) across the spectrum of cholestatic liver diseases in adults[J]. J Hepatol, 2020, 73( 3): 651- 663. DOI: 10.1016/j.jhep.2020.04.036.
[5]	FALCÃO D, PEDROTO I, MOREIRA T. The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series[J]. Dig Liver Dis, 2022, 54( 2): 221- 227. DOI: 10.1016/j.dld.2021.07.003.
[6]	NAYAGAM JS, WILLIAMSON C, JOSHI D, et al. Review article: Liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1[J]. Aliment Pharmacol Ther, 2020, 52( 11-12): 1628- 1639. DOI: 10.1111/apt.16118.
[7]	WANG HH, PORTINCASA P, LIU M, et al. Genetic analysis of ABCB4 mutations and variants related to the pathogenesis and pathophysiology of low phospholipid-associated cholelithiasis[J]. Genes, 2022, 13( 6): 1047. DOI: 10.3390/genes13061047.
[8]	van NIEKERK J, KERSTEN R, BEUERS U. Role of bile acids and the biliary HCO(3)(-) umbrella in the pathogenesis of primary biliary cholangitis[J]. Clin Liver Dis, 2018, 22( 3): 457- 479. DOI: 10.1016/j.cld.2018.03.013.
[9]	REICHERT MC, HALL RA, KRAWCZYK M, et al. Genetic determinants of cholangiopathies: Molecular and systems genetics[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864( 4 Pt B): 1484- 1490. DOI: 10.1016/j.bbadis.2017.07.029.
[10]	BAI J, LI L, LIU H, et al. A novel compound heterozygous mutation in ABCB4 gene in a pedigree with progressive familial intrahepatic cholestasis 3: A case report[J]. Ann Transl Med, 2021, 9( 5): 426. DOI: 10.21037/atm-20-3747.
[11]	AMIRNENI S, HAEP N, MA GAD, et al. Molecular overview of progressive familial intrahepatic cholestasis[J]. World J Gastroenterol, 2020, 26( 47): 7470- 7484. DOI: 10.3748/wjg.v26.i47.7470.
[12]	DONG C, CONDAT B, PICON-COSTE M, et al. Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities[J]. JHEP Rep, 2021, 3( 2): 100201. DOI: 10.1016/j.jhepr.2020.100201.
[13]	REICHERT MC, LAMMERT F. ABCB4 gene aberrations in human liver disease: An evolving spectrum[J]. Semin Liver Dis, 2018, 38( 4): 299- 307. DOI: 10.1055/s-0038-1667299.
[14]	XIAO JP, LI ZY, SONG YT, et al. Molecular pathogenesis of intrahepatic cholestasis of pregnancy[J]. Can J Gastroenterol Hepatol, 2021, 2021: 6679322. DOI: 10.1155/2021/6679322.
[15]	JACQUEMIN E, de VREE JM, CRESTEIL D, et al. The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood[J]. Gastroenterology, 2001, 120( 6): 1448- 1458. DOI: 10.1053/gast.2001.23984.
[16]	LUCENA JF, HERRERO JI, QUIROGA J, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis[J]. Gastroenterology, 2003, 124( 4): 1037- 1042. DOI: 10.1053/gast.2003.50144.
[17]	VITALE G, GITTO S, RAIMONDI F, et al. Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing[J]. J Gastroenterol, 2018, 53( 8): 945- 958. DOI: 10.1007/s00535-017-1423-1.
[18]	TERZIROLI BERETTA-PICCOLI B, THOMPSON R, FOSKETT P, et al. A heterozygous ABCB4, RUNDC3B, and ABCB1 deletion associated with severe cholestatic liver disease in adulthood[J]. Hepatology, 2019, 70( 4): 1484- 1487. DOI: 10.1002/hep.30783.
[19]	MHATRE S, WANG ZM, NAGRANI R, et al. Common genetic variation and risk of gallbladder cancer in India: A case-control genome-wide association study[J]. Lancet Oncol, 2017, 18( 4): 535- 544. DOI: 10.1016/S1470-2045(17)30167-5.
[20]	KATZENELLENBOGEN M, MIZRAHI L, PAPPO O, et al. Molecular mechanisms of liver carcinogenesis in the mdr2-knockout mice[J]. Mol Cancer Res, 2007, 5( 11): 1159- 1170. DOI: 10.1158/1541-7786.MCR-07-0172.
[21]	de VRIES E, MAZZETTI M, TAKKENBERG B, et al. Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma[J]. Liver Int, 2020, 40( 12): 3042- 3050. DOI: 10.1111/liv.14662.