中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 1
Jan.  2022
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2022  >  38(1): 154-159

Clinical and pathological features of progressive familial intrahepatic cholestasis type 3

DOI: 10.3969/j.issn.1001-5256.2022.01.024

  • Department of Hepatology, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine & Nanjing Second Hospital, Nanjing 210003, China

Research funding:

National Natural Science Foundation of China (81970454)

  • Received Date: 2021-07-26
  • Accepted Date: 2021-09-29
  • Published Date: 2022-01-20
    Abstract
  •   Objective  To investigate the clinical and pathological features of progressive familial intrahepatic cholestasis type 3 (PFIC3).  Methods  A retrospective analysis was performed for 1326 patients with unexplained liver disease who attended Nanjing Second Hospital from January 2017 to December 2019, among whom 8 patients were diagnosed with PFIC3 based on clinical/pathological manifestation and gene sequencing results (1 patient did not undergo liver biopsy due to contraindication). Clinical, laboratory, imaging, and pathological findings were analyzed and a literature review was performed for the pathology of ABCB4-related diseases to summarize the clinical and pathological features of PFIC-3.  Results  Among the 8 patients with PFIC3, there were 5 male patients and 3 female patients, with a median age of 29.5 years. Of all 8 patients, 4 (50%) manifested as chronic cholestasis and 4 (50%) manifested as biliary cirrhosis, among whom 3 (75%) had the manifestation of portal hypertension. As for biochemical examination, 75% (6/8) had an increase in alkaline phosphatase, and 100% (8/8) had an increase in gamma-glutamyl transpeptidase. As for imaging examination, 50% (4/8) had cholecystitis, 25% (2/8) had gallstones, 25% (2/8) had bile duct dilatation, 75% (6/8) had splenomegaly, and 25% (2/8) had liver cirrhosis. As for liver biopsy, all 7 patients manifested as bile duct injury and/or reduction, and 57.1% (5/7) had absence of the bile duct. Multidrug resistance P-glycoprotein 3 (MDR3) immunohistochemical staining showed normal expression in 42.9% (3/7) of the patients and reduced expression in 57.1% (4/7) of the patients. Literature review obtained 17 articles with a description of the bile duct or MDR3 immunohistochemistry. Among the 7 patients with low phospholipid-associated cholelithiasis, 71.4% (5/7) had normal bile duct, 14.3% (1/7) had bile duct reduction, and 14.3% (1/7) had absence of the bile duct; among the 6 patients with intrahepatic cholestasis of pregnancy, 16.7% (1/6) had normal bile duct, 50% (3/6) had bile duct reduction, and 33.3% (2/6) had absence of the bile duct; among the 8 patients with PFIC3, 25% (2/8) had bile duct reduction and 75% (6/8) had absence of bile duct; among the 21 patients with PFIC3, 9.5% (2/21) had normal expression of MDR3, 23.8% (5/21) had a reduction in the expression of MDR3, and 66.7% (14/21) had absence of the expression of MDR3.  Conclusion  PFIC3 mainly manifests as cholestasis, cholelithiasis, and hepatic fibrosis. Pathological manifestation includes bile duct injury and bile duct reduction or absence of the bile duct in severe cases, and the degree of injury is associated with disease severity. MDR3 immunohistochemistry may show normal expression, reduced expression, or absence of expression, and diagnosis cannot be excluded in patients with normal expression. Genetic testing can be performed for diagnosis when necessary.

     

    • FullText(HTML)
  • loading
    • References(42)
  • [1]
    BULL LN, THOMPSON RJ. Progressive familial intrahepatic cholestasis[J]. Clin Liver Dis, 2018, 22(4): 657-669. DOI: 10.1016/j.cld.2018.06.003.
    [2]
    GUNAYDIN M, BOZKURTER CIL AT. Progressive familial intrahepatic cholestasis: Diagnosis, management, and treatment[J]. Hepat Med, 2018, 10: 95-104. DOI: 10.2147/HMER.S137209.
    [3]
    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.
    [4]
    YANG YF. Road map of diagnosis in patients with unknown causes[J]. J Prac Hepatol, 2018, 21(1): 1-3. DOI: 10.3969/j.issn.1672-5069.2018.01.001.

    杨永峰. 不明原因肝病诊断思路[J]. 实用肝脏病杂志, 2018, 21(1): 1-3. DOI: 10.3969/j.issn.1672-5069.2018.01.001.
    [5]
    LIPIŃSKI P, CIARA E, JURKIEWICZ D, et al. Targeted next-generation sequencing in diagnostic approach to monogenic cholestatic liver disorders-single-center experience[J]. Front Pediatr, 2020, 8: 414. DOI: 10.3389/fped.2020.00414.
    [6]
    DENG M, GUO L, SONG YZ. Clinical and genetic analysis of a family affected by progressive familial intraphepatic cholestasis type 3[J]. Chin J Med Genetics, 2018, 35(5): 686-690. DOI: 10.3760/cma.j.issn.1003-9406.2018.05.015.

    邓梅, 郭丽, 宋元宗. 一例进行性家族性肝内胆汁淤积症3型患儿的临床及遗传学分析[J]. 中华医学遗传学杂志, 2018, 35 (5): 686-690. DOI: 10.3760/cma.j.issn.1003-9406.2018.05.015.
    [7]
    Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and treatment of cholestasis liver diseasess[J]. J Clin Hepatol, 2015, 31(12): 1989-1999. DOI: 10.3760/cma.j.issn.1007-3418.2015.12.004.

    中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 胆汁淤积性肝病诊断和治疗共识(2015)[J]. 临床肝胆病杂志, 2015, 31(12): 1989-1999. DOI: 10.3760/cma.j.issn.1007-3418.2015.12.004.
    [8]
    Chinese Society of Hepatology, Chinese Medical Association. Chinese guidelines on the management of liver cirrhosis[J]. J Clin Hepatol, 2019, 35(11): 2408-2425. DOI: 10.3760/cma.j.issn.1007-3418.2019.11.008.

    中华医学会肝病学分会. 肝硬化诊治指南[J]. 临床肝胆病杂志, 2019, 35(11): 2408-2425. DOI: 10.3760/cma.j.issn.1007-3418.2019.11.008.
    [9]
    JACQUEMIN E. Progressive familial intrahepatic cholestasis[J]. Clin Res Hepatol Gastroenterol, 2012, 36(Suppl 1): s26-s35. DOI: 10.1016/S2210-7401(12)70018-9.
    [10]
    TIAN AP, YANG YF. A comparative analysis of pathological grading and staging systems for chronic hepatitis[J]. J Clin Hepatol, 2018, 34(11): 2271-2277. DOI: 10.3969/j.issn.1001-5256.2018.11.002.

    田爱平, 杨永峰. 慢性肝炎病理学分级分期评分系统比较[J]. 临床肝胆病杂志, 2018, 34(11): 2271-2277. DOI: 10.3969/j.issn.1001-5256.2018.11.002.
    [11]
    YANG YF. Atlas of liver pathology[M]. Changsha: Central South University Publishing Group, 2018: 19-40.

    杨永峰主译. 肝脏病理学图解[M]. 长沙: 中南大学出版社, 2018: 19-40.
    [12]
    YAO GB. Clinical hepatology[M]. Shanghai: Shanghai Scientific & Technical Publishers, 2011: 344-345.

    姚光弼. 临床肝脏病学[M]. 上海: 上海科学技术出版社, 2011: 344-345.
    [13]
    FUSSEY SP, GUEST JR, JAMES OF, et al. Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis[J]. Proc Natl Acad Sci U S A, 1988, 85(22): 8654-8658. DOI: 10.1073/pnas.85.22.8654.
    [14]
    XIANG D, HE J, WANG H, et al. Liver transplantation for decompensated liver cirrhosis caused by progressive familial intrahepatic cholestasis type 3: A case report[J]. Medicine (Baltimore), 2017, 96(50): e9158. DOI: 10.1097/MD.0000000000009158.
    [15]
    GOTTHARDT D, RUNZ H, KEITEL V, et al. A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults[J]. Hepatology, 2008, 48(4): 1157-1166. DOI: 10.1002/hep.22485.
    [16]
    KHABOU B, SIALA-SAHNOUN O, GARGOURI L, et al. In silico investigation of the impact of synonymous variants in ABCB4 gene on mRNA stability/structure, splicing accuracy and codon usage: Potential contribution to PFIC3 disease[J]. Comput Biol Chem, 2016, 65: 103-109. DOI: 10.1016/j.compbiolchem.2016.10.008.
    [17]
    GOUBRAN M, ADERIBIGBE A, JACQUEMIN E, et al. Case report: Progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15 years after liver transplantation[J]. BMC Med Genet, 2020, 21(1): 238. DOI: 10.1186/s12881-020-01173-0.
    [18]
    WU Z, ZHANG S, ZHANG L, et al. Novel ABCB4 mutation in a Chinese female patient with progressive familial intrahepatic cholestasis type 3: A case report[J]. Diagn Pathol, 2020, 15(1): 39. DOI: 10.1186/s13000-020-00955-7.
    [19]
    COLOMBO C, VAJRO P, DEGIORGIO D, et al. Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations[J]. J Pediatr Gastroenterol Nutr, 2011, 52(1): 73-83. DOI: 10.1097/MPG.0b013e3181f50363.
    [20]
    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.
    [21]
    DZAGANIA T, ENGELMANN G, HÄUSSINGER D, et al. The histidine-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3[J]. Gene, 2012, 506(1): 141-145. DOI: 10.1016/j.gene.2012.06.029.
    [22]
    STICOVA E, NEROLDOVA M, KOTALOVA R, et al. ABCB4 disease mimicking morbus Wilson: A potential diagnostic pitfall[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2020, 164(1): 121-125. DOI: 10.5507/bp.2019.054.
    [23]
    BOGA S, JAIN D, SCHILSKY ML. Presentation of progressive familial intrahepatic cholestasis type 3 mimicking wilson disease: Molecular genetic diagnosis and response to treatment[J]. Pediatr Gastroenterol Hepatol Nutr, 2015, 18(3): 202-208. DOI: 10.5223/pghn.2015.18.3.202.
    [24]
    GIOVANNONI I, SANTORELLI FM, CANDUSSO M, et al. Two novel mutations in African and Asian children with progressive familial intrahepatic cholestasis type 3[J]. Dig Liver Dis, 2011, 43(7): 567-570. DOI: 10.1016/j.dld.2011.03.004.
    [25]
    de VREE JM, JACQUEMIN E, STURM E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis[J]. Proc Natl Acad Sci U S A, 1998, 95(1): 282-287. DOI: 10.1073/pnas.95.1.282.
    [26]
    WENDUM D, BARBU V, ROSMORDUC O, et al. Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations[J]. Virchows Arch, 2012, 460(3): 291-298. DOI: 10.1007/s00428-012-1202-6.
    [27]
    FANG LJ, WANG XH, KNISELY AS, et al. Chinese children with chronic intrahepatic cholestasis and high γ-glutamyl transpeptidase: Clinical features and association with ABCB4 mutations[J]. J Pediatr Gastroenterol Nutr, 2012, 55(2): 150-156. DOI: 10.1097/MPG.0b013e31824ef36f.
    [28]
    ZIOL M, BARBU V, ROSMORDUC O, et al. ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults[J]. Gastroenterology, 2008, 135(1): 131-141. DOI: 10.1053/j.gastro.2008.03.044.
    [29]
    VIJ M, VALAMPARAMPIL J, SHANMUGUM N, et al. Paucity of interlobular bile ducts in Multidrug-Resistant P-Glycoprotein 3 (MDR3) deficiency[J]. Int J Surg Pathol, 2019, 27(3): 343-347. DOI: 10.1177/1066896918799941.
    [30]
    FRIDER B, CASTILLO A, GORDO-GILART R, et al. Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MDR3[J]. Ann Hepatol, 2015, 14(5): 745-751.
    [31]
    SANNIER A, GANNE N, TEPPER M, et al. MDR3 immunostaining on frozen liver biopsy samples is not a sensitive diagnostic tool for the detection of heterozygous MDR3/ABCB4 gene mutations[J]. Virchows Arch, 2012, 460(5): 535-537; author reply 539. DOI: 10.1007/s00428-012-1231-1.
    [32]
    GOTTHARDT D, RUNZ H, KEITEL V, et al. A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults[J]. Hepatology, 2008, 48(4): 1157-1166. DOI: 10.1002/hep.22485.
    [33]
    FOMBUENA B, AMPUERO J, ÁLVAREZ L, et al. LPAC syndrome associated with deletion of the full exon 4 in a ABCB4 genetic mutation in a patient with hepatitis C[J]. Rev Esp Enferm Dig, 2014, 106(8): 544-547.
    [34]
    ROSMORDUC O, HERMELIN B, BOELLE PY, et al. ABCB4 gene mutations and primary sclerosing cholangitis[J]. Gastroenterology, 2004, 126(4): 1220-1222; author reply 1222-1223. DOI: 10.1053/j.gastro.2004.02.042.
    [35]
    DAVIT-SPRAUL A, GONZALES E, BAUSSAN C, et al. The spectrum of liver diseases related to ABCB4 gene mutations: Pathophysiology and clinical aspects[J]. Semin Liver Dis, 2010, 30(2): 134-146. DOI: 10.1055/s-0030-1253223.
    [36]
    MOROTTI RA, SUCHY FJ, MAGID MS. Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: A review of the liver pathology findings[J]. Semin Liver Dis, 2011, 31(1): 3-10. DOI: 10.1055/s-0031-1272831.
    [37]
    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.
    [38]
    THOENI C, WALDHERR R, SCHEUERER J, et al. Expression analysis of ATP-binding cassette transporters ABCB11 and ABCB4 in primary sclerosing cholangitis and variety of pediatric and adult cholestatic and noncholestatic liver diseases[J]. Can J Gastroenterol Hepatol, 2019, 2019: 1085717. DOI: 10.1155/2019/1085717.
    [39]
    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.
    [40]
    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.
    [41]
    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.
    [42]
    COLOMBO C, VAJRO P, DEGIORGIO D, et al. Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations[J]. J Pediatr Gastroenterol Nutr, 2011, 52(1): 73-83. DOI: 10.1097/MPG.0b013e3181f50363.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)  / Tables(4)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (916) PDF downloads(100) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return