胆汁淤积性肝病“上升”病理生理学模式及用药合理性探讨

Rationality of medication based on the “ascending” pathophysiology of cholestatic liver disease

近年来,有学者提出胆汁淤积性肝病具有"上升"病理生理学模式,尤其是在原发性胆汁性胆管炎和原发性硬化性胆管炎中。该理论认为,胆汁淤积性肝病在病变过程中随时间推延,在解剖结构上呈自下而上发展。原发或早期病灶通常位于"下游"的胆管,主要病因可能为免疫介导的胆管坏死性炎症损伤;当发生胆汁淤积时,胆盐介导的毒性作用将导致"上游"的肝实质损伤,因此胆汁毒性在疾病进展期间显得更为重要。基于其"上升"病理生理学模式,可以看到不同阶段的发病部位及病因均不同,因此有必要对胆汁淤积性肝病进行分期,并根据不同疾病阶段选取不同治疗药物,以更有效的方式利用现有药物,并为新药开发指明方向。然而,目前尚缺乏胆汁淤积性肝病早期生化标志物,寻找特异性强、敏感度高的生化标志物是目前临床的主要工作。

In recent years,some scholars have put forward the“ascending”pathophysiology of cholestatic liver disease,especially in primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC).According to this theory,cholestatic liver disease develops from the bottom to the top of the anatomical structure over time.Primary or early lesions are usually located in the“downstream”bile duct,with a major cause of immune-mediated biliary necrotizing inflammatory injury.When cholestasis occurs,the toxic effect mediated by bile salt will lead to the injury in the“upstream”liver parenchyma.Therefore,bile toxicity is of great importance during disease progression.According to this theory of“ascending”pathophysiology,there are different locations and causes of the disease in different disease stages,and therefore,it is necessary to establish a staging system for cholestatic liver disease and use different drugs in different stages,in order to use the existing drugs in a more effective manner and give directions for new drug development.However,there are still no early biochemical markers for cholestatic liver disease,and current clinical work should focus on the search for biomarkers with strong specificity and high sensitivity.