Cellular mechanisms of intrahepatic cholestasis.

Most forms of intrahepatic cholestasis are caused by a failure of hepatocytes to secrete osmotically active bile constituents into the minute channels of bile canaliculi. This overall vectorial bile secretory process is dependent upon a variety of polarised active transport functions at the basolateral (sinusoidal and lateral) and canalicular plasma membrane domains, as well as upon the coordinated vectorial movement of intracellular vesicles. Although considerable progress has been made in recent years in the identification, characterisation and exact localisation of a number of polarised hepatocellular transport systems, the primary mechanisms and targets leading to defective bile secretion and cholestasis are still not completely understood. For example, not all reported experimental data are compatible with the concept that estrogen-induced cholestasis represents a predominant sinusoidal disease process. In addition, the pathophysiological significance of disturbed transcytotic pathways and/or disrupted intracellular calcium homeostasis are not yet clear. For many forms of cholestasis, it remains uncertain as to whether leaky tight junctions represent a primary cause rather than a secondary phenomenon of the cholestatic state. However, the ongoing progress in the understanding of the normal mechanisms involved in the establishment, maintenance and regulation of ion homeostasis and polar transport functions in hepatocytes will, undoubtedly, improve our knowledge of the pathogenesis of intrahepatic cholestasis and, it is hoped, lead to better therapeutic strategies in the near future.