胆汁酸–肠道–免疫轴视角下原发性胆汁性胆管炎相关骨质疏松的研究进展与临床管理启示

Research Progress and Clinical Management Implications of Primary Biliary Cholangitis-Associated Osteoporosis from the Perspective of the Bile Acid-Gut-Immune Axis

摘要: 原发性胆汁性胆管炎(PBC)属于慢性胆汁淤积性肝病。该病以肝内小胆管的免疫介导性损伤为主要病理基础。临床随访资料显示，除肝脏受累外，一部分患者会逐渐出现骨量下降或骨质疏松。过去，临床医生常把这一问题归因为疾病晚期表现。医生通常在患者发生骨折或进入终末期阶段后才启动相关评估。而现有临床数据表明，即使患者肝功能仍处于代偿期，骨代谢异常也可能已经出现。上述现象说明，骨损害的形成并不完全依赖终末期肝功能衰竭。近年的基础与临床研究重新开始关注胆汁酸的信号在这一致病过程中的作用。研究人员发现，胆汁酸不仅参与脂类消化吸收，还通过FXR、TGR5等受体参与代谢调节和免疫反应。在PBC患者体内，胆汁淤积会改变胆汁酸组成，同时维持低度免疫活化状态。上述变化可能通过肠道环境改变和炎症通路影响骨重建过程。多项队列研究结果显示，PBC人群发生骨质疏松和骨折的比例高于普通人群。不过，这种风险升高并未与肝病分期完全一致。在日常随访过程中，临床团队通常把重点放在生化指标和疾病进展评估上。骨健康监测在多数情况下处于次要位置。部分医疗机构仅在骨密度明显下降后才考虑干预。这样做可能使部分早期高风险患者未被及时识别。临床管理体系可以在常规复查中加入骨代谢相关指标。医生通过增加相关监测项目，可以更早发现骨折风险。

Abstract: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by immune-mediated injury of the small intrahepatic bile ducts. Long-term clinical follow-up has shown that, in addition to hepatic involvement, a proportion of patients gradually develop reduced bone mass or osteoporosis. In the past, clinicians often regarded skeletal complications as a late manifestation of advanced disease and typically initiated evaluation only after fractures occurred or when patients had progressed to end-stage liver failure. However, recent clinical researches indicate that abnormalities in bone metabolism may occurred while hepatic function remains in a compensated state. These observations suggest that bone impairment does not only rely on terminal hepatic insufficiency. In recent years, both basic and clinical research have revealed the role of bile acid signal in this pathogenic process. Bile acids are now recognized not only as mediators of lipid digestion and absorption but also as signaling molecules that regulate metabolic homeostasis and immune responses through receptors such as FXR and TGR5. In patients with PBC, cholestasis alters bile acid composition and sustains a state of low-grade immune activation. These changes may influence bone remodeling through modifications of the intestinal microenvironment and activation of inflammatory pathways. Several cohort studies have reported that the prevalence of osteoporosis and fractures is higher in individuals with PBC than in the general population. Notably, the magnitude of this increased risk does not appear to parallel liver disease stage in a strictly linear manner. During routine follow-up, clinical teams tend to focus primarily on assessment of hepatic disease progression and pay less attention to skeletal status. In some centers, intervention is considered only after a substantial decline in bone mineral density has been documented. This approach may delay the identification of patients at elevated fracture risk in earlier stages. Incorporating bone metabolism-related parameters into standard follow-up protocols could facilitate earlier recognition of skeletal vulnerability and enable more timely preventive strategies.