Mechanisms of cholestasis.
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.
Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland. kullak@kpt.unizh.ch
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D017209:Apoptosis / Q000502:physiology; D001647:Bile Acids and Salts / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use; D002779:Cholestasis / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D001651:Cholestasis, Extrahepatic / Q000503:physiopathology; D004958:Estradiol / Q000009:adverse effects; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D010288:Parenteral Nutrition / Q000009:adverse effects; D013577:Syndrome
D001647:Bile Acids and Salts; D017665:Hydroxyl Radical; D004958:Estradiol