原发性胆汁性胆管炎的治疗进展

吕行; 李婷; 孙晓东; 周建鹏; 王东霞; 吕国悦

doi:10.3969/j.issn.1001-5256.2022.09.035

原发性胆汁性胆管炎的治疗进展

DOI: 10.3969/j.issn.1001-5256.2022.09.035

吉林大学第一医院肝胆胰外一科，长春 130021

基金项目:

国家自然科学基金 (U20A20360);

吉林省科技厅项目 (20200603001SF)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：吕行、李婷负责收集数据，资料分析，撰写论文；孙晓东、周建鹏、王东霞负责修改文章；吕国悦提供写作思路，指导撰写文章，修改文章并最后定稿。

详细信息

通信作者:
吕国悦，lvgy@jlu.edu.cn

计量
- 文章访问数: 585
- HTML全文浏览量: 616
- PDF下载量: 110
- 被引次数: 0
出版历程
- 收稿日期: 2022-03-01
- 录用日期: 2022-04-04
- 出版日期: 2022-09-20

Research advances in the treatment of primary biliary cirrhosis

First Department of Hepatopancreatobiliary Surgery, The First Hospital of Jilin University, Changchun 130021, China

Research funding:

National Natural Science Foundation of China (U20A20360);

Science and Technology Department of Jilin Province (20200603001SF)

More Information

Corresponding author: LYU Guoyue, lvgy@jlu.edu.cn(ORCID: 0000-0002-9778-5080)

摘要

摘要: 原发性胆汁性胆管炎(PBC)是一种自身免疫性疾病，常见于中年女性。疾病进展可导致肝硬化、肝衰竭。熊去氧胆酸和奥贝胆酸为美国食品药品管理局唯一批准的一、二线用药，但是约有40%的患者对熊去氧胆酸应答不敏感，多种二线用药如贝特类药物、免疫抑制剂的研究正在开展，而肝移植是终末期PBC治疗的唯一手段。本文就PBC近年来的治疗研究进展及相关机制进行综述，旨在为临床实践提供参考。
- 原发性胆汁性胆管炎 /
- 药物疗法 /
- 肝移植
Abstract: Primary biliary cholangitis (PBC) is an autoimmune disease commonly observed in middle-aged women, and it may progress to liver cirrhosis and liver failure. Ursodeoxycholic acid and obeticholic acid are the only first - and second-line drugs approved by the FDA, but about 40% of patients are insensitive to UDCA. Studies are being conducted on a variety of second-line drugs such as fibrates and immunosuppressive drugs, and liver transplantation is the only treatment method for end-stage PBC. This article reviews the research advances in the treatment of PBC and related mechanisms, in order to provide a reference for clinical practice.
- Primary Biliary Cholangitis /
- Drug Therapy /
- Liver Transplantation

HTML全文

图 1 PBC诊治流程

注：AMA，抗线粒体抗体；ANA，抗核抗体。

Figure 1. Diagnosis and treatment flow chart of PBC

下载: 全尺寸图片幻灯片

参考文献(50)

[1]	SHIMODA S, TANAKA A. It is time to change primary biliary cirrhosis (PBC): New nomenclature from "cirrhosis" to "cholangitis", and upcoming treatment based on unveiling pathology[J]. Hepatol Res, 2016, 46(5): 407-415. DOI: 10.1111/hepr.12615.
[2]	TRIVEDI PJ, LAMMERS WJ, van BUUREN HR, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study[J]. Gut, 2016, 65(2): 321-329. DOI: 10.1136/gutjnl-2014-308351.
[3]	ZHANG FC, WANG L, SHUAI ZW, et al. Recommendations for diagnosis and treatment of primary biliary cholangitis in China (2021)[J]. Chin J Intern Med, 2021, 60(8): 709-715. DOI: 10.3760/cma.j.cn112138-20210520-00360. 张奉春, 王立, 帅宗文, 等. 原发性胆汁性胆管炎诊疗规范(2021)[J]. 中华内科杂志, 2021, 60(8): 709-715. DOI: 10.3760/cma.j.cn112138-20210520-00360.
[4]	TANAKA A, MORI M, MATSUMOTO K, et al. Increase trend in the prevalence and male-to-female ratio of primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis in Japan[J]. Hepatol Res, 2019, 49(8): 881-889. DOI: 10.1111/hepr.13342.
[5]	LLEO A, OERTELT-PRIGIONE S, BIANCHI I, et al. Y chromosome loss in male patients with primary biliary cirrhosis[J]. J Autoimmun, 2013, 41: 87-91. DOI: 10.1016/j.jaut.2012.12.008.
[6]	TANAKA A, LEUNG P, GERSHWIN ME. The genetics of primary biliary cholangitis[J]. Curr Opin Gastroenterol, 2019, 35(2): 93-98. DOI: 10.1097/MOG.0000000000000507.
[7]	ZENG N, DUAN W, CHEN S, et al. Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis[J]. Hepatol Int, 2019, 13(6): 788-799. DOI: 10.1007/s12072-019-09984-x.
[8]	CORPECHOT C, CHAZOUILLōRES O, ROUSSEAU A, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis[J]. N Engl J Med, 2018, 378(23): 2171-2181. DOI: 10.1056/NEJMoa1714519.
[9]	HONDA A, TANAKA A, KANEKO T, et al. Bezafibrate improves GLOBE and UK-PBC scores and long-term outcomes in patients with primary biliary cholangitis[J]. Hepatology, 2019, 70(6): 2035-2046. DOI: 10.1002/hep.30552.
[10]	ÖRNOLFSSON KT, OLAFSSON S, BERGMANN OM, et al. Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis[J]. Hepatology, 2018, 68(1): 166-171. DOI: 10.1002/hep.29675.
[11]	WAGNER M, FICKERT P. Drug therapies for chronic cholestatic liver diseases[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 503-527. DOI: 10.1146/annurev-pharmtox-010818-021059.
[12]	TANG R, WEI Y, LI Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy[J]. Gut, 2018, 67(3): 534-541. DOI: 10.1136/gutjnl-2016-313332.
[13]	GAO B, LIN BL. Research progress on the relationship between intestinal microbe and primary biliary cholangitis[J]. Chin J Infect Dis, 2020, 38(12): 841-844. DOI: 10.3760/cma.j.cn311365-20191120-00383. 高斌, 林炳亮. 肠道微生物与原发性胆汁性胆管炎关系的研究进展[J]. 中华传染病杂志, 2020, 38(12): 841-844. DOI: 10.3760/cma.j.cn311365-20191120-00383.
[14]	LI B, ZHANG J, CHEN Y, et al. Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary cholangitis[J]. Gut Microbes, 2021, 13(1): 1946366. DOI: 10.1080/19490976.2021.1946366.
[15]	FRIEDMAN ES, LI Y, SHEN TD, et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid[J]. Gastroenterology, 2018, 155(6): 1741-1752. DOI: 10.1053/j.gastro.2018.08.022.
[16]	TERZIROLI BERETTA-PICCOLI B, MIELI-VERGANI G, VERGANI D, et al. The challenges of primary biliary cholangitis: What is new and what needs to be done[J]. J Autoimmun, 2019, 105: 102328. DOI: 10.1016/j.jaut.2019.102328.
[17]	YOU H, MA X, EFE C, et al. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis[J]. Hepatol Int, 2022, 16(1): 1-23. DOI: 10.1007/s12072-021-10276-6.
[18]	GOSSARD AA, LINDOR KD. Current and promising therapy for primary biliary cholangitis[J]. Expert Opin Pharmacother, 2019, 20(9): 1161-1167. DOI: 10.1080/14656566.2019.1601701.
[19]	HARMS MH, VAN BUUREN HR, CORPECHOT C, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis[J]. J Hepatol, 2019, 71(2): 357-365. DOI: 10.1016/j.jhep.2019.04.001.
[20]	CAI J, SUN L, GONZALEZ FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis[J]. Cell Host Microbe, 2022, 30(3): 289-300. DOI: 10.1016/j.chom.2022.02.004.
[21]	NEVENS F, ANDREONE P, MAZZELLA G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis[J]. N Engl J Med, 2016, 375(7): 631-643. DOI: 10.1056/NEJMoa1509840.
[22]	TRAUNER M, NEVENS F, SHIFFMAN ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study[J]. Lancet Gastroenterol Hepatol, 2019, 4(6): 445-453. DOI: 10.1016/S2468-1253(19)30094-9.
[23]	PANDIT S, SAMANT H. Primary biliary cholangitis[M]. Treasure Island (FL): StatPearls Publishing, 2022.
[24]	XIA ZY, HAN T, MENG HJ. Clinical effect of early immunosuppression combined with ursodeoxycholic acid in treatment of primary biliary cirrhosis[J]. Clin J Med Offic, 2020, 48(1): 97-98, 101. DOI: 10.16680/j.1671-3826.2020.01.33. 夏志勇, 韩涛, 孟红军. 早期免疫抑制联合熊去氧胆酸治疗原发性胆汁性肝硬化临床疗效[J]. 临床军医杂志, 2020, 48(1): 97-98, 101. DOI: 10.16680/j.1671-3826.2020.01.33.
[25]	WANG L, SUN K, TIAN A, et al. Fenofibrate improves GLOBE and UK-PBC scores and histological features in primary biliary cholangitis[J]. Minerva Med, 2021. DOI: 10.23736/S0026-4806.21.07316-X.[Online ahead of print]
[26]	HEGADE VS, KENDRICK SF, DOBBINS RL, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study[J]. Lancet, 2017, 389(10074): 1114-1123. DOI: 10.1016/S0140-6736(17)30319-7.
[27]	WESTEROUEN VAN MEETEREN MJ, DRENTH J, TJWA E. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH)[J]. Expert Opin Investig Drugs, 2020, 29(2): 117-123. DOI: 10.1080/13543784.2020.1668375.
[28]	SCHATTENBERG JM, PARES A, KOWDLEY KV, et al. A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA[J]. J Hepatol, 2021, 74(6): 1344-1354. DOI: 10.1016/j.jhep.2021.01.013.
[29]	ARENAS F, HERVÍAS I, SÁEZ E, et al. Promoter hypermethylation of the AE2/SLC4A2 gene in PBC[J]. JHEP Rep, 2019, 1(3): 145-153. DOI: 10.1016/j.jhepr.2019.05.006.
[30]	ARENAS F, HERVIAS I, URIZ M, et al. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells[J]. J Clin Invest, 2008, 118(2): 695-709. DOI: 10.1172/JCI33156.
[31]	HIRSCHFIELD GM, BEUERS U, KUPCINSKAS L, et al. A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA[J]. J Hepatol, 2021, 74(2): 321-329. DOI: 10.1016/j.jhep.2020.09.011.
[32]	VETTER M, KREMER AE. Primary biliary cholangitis-established and novel therapies[J]. Internist (Berl), 2018, 59(6): 544-550. DOI: 10.1007/s00108-018-0427-0.
[33]	MYERS RP, SWAIN MG, LEE SS, et al. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid[J]. Am J Gastroenterol, 2013, 108(6): 933-941. DOI: 10.1038/ajg.2013.51.
[34]	TSUDA M, MORITOKI Y, LIAN ZX, et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid[J]. Hepatology, 2012, 55(2): 512-521. DOI: 10.1002/hep.24748.
[35]	ZHAN K, XU Y, HAN ML, et al. Mechanism of action of Daifan powder in the prevention and treatment of primary biliary cholangitis via its interventional effect on Th17/Treg balance[J]. J Clin Hepatol, 2018, 34(11): 2373-2378. DOI: 10.3969/j.issn.1001-5256.2018.11.021. 占凯, 徐燕, 韩梦玲, 等. 黛矾散干预Th17/Treg平衡防治原发性胆汁性胆管炎的作用机制[J]. 临床肝胆病杂志, 2018, 34(11): 2373-2378. DOI: 10.3969/j.issn.1001-5256.2018.11.021.
[36]	ZHAO LL, CHEN ZL, ZHANG FC. Combination therapy of mycophenolate mofetil and ursodeoxycholic acid for the treatment of patients with incomplete response to ursodeoxycholic acid in primary biliary cirrhosis[J]. Chin J Rheumatol, 2020, 24(10): 664-669. DOI: 10.3760/cma.j.c141217-20191217-00427. 赵丽伶, 陈志磊, 张奉春. 吗替麦考酚酯在对熊去氧胆酸应答不佳的原发性胆汁性胆管炎患者中的应用[J]. 中华风湿病学杂志, 2020, 24(10): 664-669. DOI: 10.3760/cma.j.c141217-20191217-00427.
[37]	ZHU GQ, HUAND S, HUANG GQ, et al. Optimal drug regimens for primary biliary cirrhosis: a systematic review and network meta-analysis[J]. Oncotarget, 2015, 6(27): 24533-49. DOI: 10.18632/oncotarget.4528.
[38]	GULAMHUSEIN AF, HIRSCHFIELD GM. Primary biliary cholangitis: pathogenesis and therapeutic opportunities[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(2): 93-110. DOI: 10.1038/s41575-019-0226-7.
[39]	CORPECHOT C, CHRÉTIEN Y, CHAZOUILLōRES O, et al. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis[J]. J Hepatol, 2010, 53(1): 162-169. DOI: 10.1016/j.jhep.2010.02.019.
[40]	CORPECHOT C, GAOUAR F, CHRÉTIEN Y, et al. Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis[J]. J Hepatol, 2012, 56(1): 218-224. DOI: 10.1016/j.jhep.2011.03.031.
[41]	KIM KA, KIM YS, PARK SH, et al. Environmental risk factors and comorbidities of primary biliary cholangitis in Korea: a case-control study[J]. Korean J Intern Med, 2021, 36(2): 313-321. DOI: 10.3904/kjim.2019.234.
[42]	PATEL R, PORTONE G, LAMBERT JA, et al. Disease-modifying therapies and symptomatic management for primary biliary cholangitis[J]. Br J Hosp Med (Lond), 2021, 82(11): 1-9. DOI: 10.12968/hmed.2021.0247.
[43]	WANG L, HAN Y. An excerpt of primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases[J]. J Clin Hepatol, 2018, 34(11): 2300-2304. DOI: 10.3969/j.issn.1001-5256.2018.11.007. 王璐, 韩英. 《2018年美国肝病学会原发性胆汁性胆管炎实践指导》摘译[J]. 临床肝胆病杂志, 2018, 34(11): 2300-2304. DOI: 10.3969/j.issn.1001-5256.2018.11.007.
[44]	ADAM R, KARAM V, DELVART V, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR)[J]. J Hepatol, 2012, 57(3): 675-688. DOI: 10.1016/j.jhep.2012.04.015.
[45]	CARBONE M, BUFTON S, MONACO A, et al. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study[J]. J Hepatol, 2013, 59(3): 490-494. DOI: 10.1016/j.jhep.2013.04.017.
[46]	MONTANO-LOZA AJ, HANSEN BE, CORPECHOT C, et al. Factors associated with recurrence of primary biliary cholangitis after liver transplantation and effects on graft and patient survival[J]. Gastroenterology, 2019, 156(1): 96-107. DOI: 10.1053/j.gastro.2018.10.001.
[47]	LEUNG KK, DEEB M, HIRSCHFIELD GM. Review article: pathophysiology and management of primary biliary cholangitis[J]. Aliment Pharmacol Ther, 2020, 52(7): 1150-1164. DOI: 10.1111/apt.16023.
[48]	LI X, PENG J, OUYANG R, et al. Risk factors for recurrent primary biliary cirrhosis after liver transplantation: A systematic review and meta-analysis[J]. Dig Liver Dis, 2021, 53(3): 309-317. DOI: 10.1016/j.dld.2020.12.005.
[49]	CORPECHOT C, CHAZOUILLōRES O, BELNOU P, et al. Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis[J]. J Hepatol, 2020, 73(3): 559-565. DOI: 10.1016/j.jhep.2020.03.043.
[50]	BALAN V, RUPPERT K, DEMETRIS AJ, et al. Long-term outcome of human leukocyte antigen mismatching in liver transplantation: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database[J]. Hepatology, 2008, 48(3): 878-888. DOI: 10.1002/hep.22435.