胆汁淤积性肝病精准诊疗与前沿探索

张樑君; 潘琼; 柴进

doi:10.12449/JCH250701

胆汁淤积性肝病精准诊疗与前沿探索

DOI: 10.12449/JCH250701

陆军军医大学（第三军医大学）第一附属医院消化内科，胆汁淤积肝病中心，代谢相关脂肪性肝病医学研究中心，重庆 400038

基金项目:

国家自然科学基金杰出青年基金 (82325008);

国家自然科学基金原创探索计划项目 (82450104)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：张樑君负责查阅和归纳文献并撰写论文；潘琼、柴进负责指导撰写并修改论文。

详细信息

通信作者:
柴进， jin.chai@cldcsw.org （ORCID： 0000-0002-8543-4566）

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出版历程
- 收稿日期: 2025-04-19
- 录用日期: 2025-05-31
- 出版日期: 2025-07-25

Precision diagnosis and treatment of cholestatic liver disease and frontier exploration

Department of Gastroenterology，The First Affiliated Hospital of Army Medical University （Third Military Medical University），Cholestatic Liver Diseases Center，Metabolic Dysfunction-Associated Steatotic Liver Disease Medical Research Center，Chongqing 400038，China

Research funding:

National Natural Science Foundation of China for Outstanding Young Scholars (82325008);

Original Exploration Program of the National Science Foundation of China (82450104)

More Information

Corresponding author: CHAI Jin， jin.chai@cldcsw.org （ORCID： 0000-0002-8543-4566）

摘要

摘要: 胆汁淤积性肝病（CLD）包括一系列急性和慢性疾病，其特征是胆汁形成和/或流动受损，若未及时治疗可能进展为肝硬化甚至肝衰竭。近年来，随着分子生物学和组学技术的发展，CLD的诊断与治疗正向精准医学迈进。本文综述了CLD在基因检测、多组学生物标志物等方面的诊断进展，系统梳理了亲水胆汁酸、FXR激动剂、PPAR激动剂、抗生素与新兴分子靶向治疗的最新研究与临床试验。未来，整合多维组学数据、推动个体化诊疗模式将是CLD精准医学发展的关键方向。本文旨在为该领域的基础研究与临床转化提供前瞻性参考。
- 胆汁淤积 /
- 精准医学 /
- 诊断 /
- 治疗学
Abstract: Cholestatic liver disease （CLD） encompasses a range of acute and chronic disorders characterized by impaired bile formation and/or flow. If left untreated， it may progress to cirrhosis and even liver failure. In recent years， with the development of molecular biology and omics technologies， the diagnosis and treatment of CLD are entering the era of precision medicine. This article reviews the advances in the diagnosis of CLD based on genetic testing and omics biomarkers and summarizes the latest studies and clinical trials on hydrophilic bile acid， FXR agonist， PPAR agonist， antibiotics， and novel molecules in targeted therapy for CLD. In the future， integrating omics data and implementing individualized diagnosis and treatment will be the main directions in precision medicine for CLD. This article aims to provide a reference for basic research and clinical translation in the field of CLD.
- Cholestasis /
- Precision Medicine /
- Diagnosis /
- Therapeutics

HTML全文

表 1 CLD的当前和新兴药物治疗

Table 1. Current and emerging drug therapies for CLD

药物名称	治疗靶点/机制	适应证	研发阶段/状态	备注
现有药物
UDCA	亲水性胆汁酸，替代细胞毒性胆汁酸，保护胆管细胞	PBC（一线）	已批准（1997年 FDA）	长期使用，需监测生化反应
OCA	FXR激动剂，调节胆汁酸代谢	PBC（二线）	加速批准（2016年 FDA）	临床获益未完全证实（COBALT试验失败），于2024年在欧洲撤市
SAMe	转甲基/转硫基作用	ICP和药物性胆汁淤积	已批准
贝特类（非诺贝特、苯扎贝特）	非诺贝特为PPARα激动剂，苯扎贝特为泛PPAR激动剂（α/δ/γ），调控胆汁代谢和抗炎通路	PBC（二线）	部分国家批准（如日本、欧洲）	美国仅非诺贝特可用，需监测肝酶水平
布地奈德	糖皮质激素，抗炎作用	PBC（辅助）	临床试验/超适应证使用	疗效存疑，可能用于PBC-AIH 重叠
考来烯胺	胆汁酸螯合剂，减少胆汁酸肠肝循环	PBC瘙痒	已批准	需与其他药物间隔服用
利福平	PXR激动剂，调节胆汁酸代谢	PBC瘙痒（二线）	超适应证使用	可能引起肝毒性
纳曲酮	阿片受体拮抗剂，缓解瘙痒	PBC瘙痒（三线）	超适应证使用	需逐步增加剂量以避免戒断反应
新兴疗法
Elafibranor	双重PPARα/δ激动剂，调节胆汁酸代谢和抗炎	PBC	已批准（联合UDCA）（2024年FDA）	改善ALP水平和瘙痒，副作用包括腹泻
Seladelpar	选择性PPARδ激动剂，抑制胆汁酸合成和炎症因子	PBC	加速批准（2024年 FDA）	显著降低ALP水平，改善瘙痒和睡眠
Saroglitazar	PPARα/γ双重激动剂，可抗胆汁淤积、抗炎与抗纤维化	PBC	Ⅲ期临床试验（NCT05133336）	部分患者出现肝酶水平升高，需优化剂量
Setanaxib	NOX1/4抑制剂，减少活性氧的产生，可抗纤维化	PBC	Ⅱ期临床试验（NCT05014672）	显著降低ALP水平，改善疲劳评分
Nor-UDCA	C23同源UDCA，具有抗炎与抗纤维化作用，且可促进胆酸分流	PSC	Ⅲ期试验（NCT02872921）	降低ALP水平
Cilofexor	非胆汁酸类FXR激动剂，调节胆汁酸代谢	PSC	Ⅲ期终止	无效
Berberine Ursode‑ oxycholate （HTD1801）	UDCA+小檗碱复合物，具有抗菌和抗炎的作用	PSC	Ⅱ期试验	降低ALP水平，安全性较好
Bexotegrast	αvβ6/αvβ1整合素抑制剂，通过抑制TGF-β抗纤维化	PSC	Ⅱa期试验（INTEGRIS-PSC）	改善纤维化标志物
Linerixibat/ Maralixibat	回肠胆汁酸转运体抑制剂，抑制回肠对胆汁酸的重吸收	PBC/PSC 瘙痒	Ⅱ/Ⅲ期试验（GLIMMER试验）	改善瘙痒和睡眠障碍
辛伐他汀（Simvastatin）	HMG-CoA还原酶抑制剂，具有潜在抗炎和抗纤维化的作用	PSC	Ⅲ期试验（NCT04133792）	可能降低肝移植或死亡风险
FGF19类似物（NGM282）	FGF19类似物，抑制CYP7A1，减少胆汁酸合成	PBC/PSC	Ⅱ期试验	降低ALP水平，但需关注肝细胞癌风险
粪菌移植/口服万古霉素	调节肠道菌群	PSC	证据不足	粪菌移植缺乏大样本证据；万古霉素为小样本研究
注：FDA，美国食品药品监督管理局；SAMe，Ｓ-腺苷蛋氨酸。

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