Kullak-Ublick G A, Meier P J
Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland.
Clin Liver Dis. 2000 May;4(2):357-85. doi: 10.1016/s1089-3261(05)70114-8.
From the multiple mechanisms of cholestasis presented in this article, a unifying hypothesis may be deduced by parsimony. The disturbance of the flow of bile must inevitably lead to the intracellular retention of biliary constituents. Alternatively, the lack of specific components of bile unmasks the toxic potential of other components, as in the case of experimental mdr2 deficiency. In the sequence of events that leads to liver injury, the cytotoxic action of bile salts is pivotal to all forms of cholestasis. The inhibition of the bsep by drugs, sex steroids, or monohydroxy bile salts is an example of direct toxicity to the key mediator in canalicular bile salt excretion. In other syndromes, the dysfunction of distinct hepatocellular transport systems is the primary pathogenetic defect leading to cholestasis. Such dysfunctions include the genetic defects in PFIC and the direct inhibition of gene transcription by cytokines. Perturbations in the short-term regulation of transport protein function are exemplified by the cholestasis of endotoxinemia. The effect of bile salts on signal transduction, gene transcription, and transport processes in hepatocytes and cholangiocytes has become the focus of intense research in recent years. The central role of bile salts in the pathogenesis of cholestasis has, ironically, become all the more evident from the improvement of many cholestatic syndromes with oral bile salt therapy.
从本文所呈现的胆汁淤积的多种机制中，可以通过简约法推导出一个统一的假说。胆汁流动的紊乱必然会导致胆汁成分在细胞内潴留。或者，胆汁中特定成分的缺乏会使其他成分的毒性潜力暴露出来，就像实验性多药耐药蛋白2（mdr2）缺乏的情况一样。在导致肝损伤的一系列事件中，胆盐的细胞毒性作用对所有形式的胆汁淤积都至关重要。药物、性类固醇或单羟基胆盐对胆盐输出泵（bsep）的抑制是对胆小管胆盐排泄关键介质直接毒性的一个例子。在其他综合征中，不同肝细胞转运系统的功能障碍是导致胆汁淤积的主要致病缺陷。此类功能障碍包括进行性家族性肝内胆汁淤积症（PFIC）中的基因缺陷以及细胞因子对基因转录的直接抑制。内毒素血症性胆汁淤积就是转运蛋白功能短期调节受到干扰的一个例子。近年来，胆盐对肝细胞和胆管细胞中信号转导、基因转录及转运过程的影响已成为深入研究的焦点。具有讽刺意味的是，从许多胆汁淤积综合征通过口服胆盐治疗得到改善的情况来看，胆盐在胆汁淤积发病机制中的核心作用变得更加明显了。
