Medical treatment of cholestatic liver diseases:From pathobiology to pharmacological targets

胆汁分泌物依赖于很多个肝胆管运输系统的协调函数。胆汁郁积可以被胆汁分泌物，胆汁流动的阻塞或二的联合的一个缺陷引起。胆汁郁积的所有形式的普通后果在导致 hepatocytes 并且最后的 apoptosis 或坏死到长期的胆汁郁积的肝疾病的 hepatocytes 是胆汁酸和另外的潜在地有毒的混合物的保留。在某些胆汁郁积的混乱，也有进仙子的胆汁酸的漏胆汁的空间引起门发炎和纤维变性。为肝内胆汁郁积的处理的下列药理学目标能被识别：身体笔直的胆汁的分泌物的刺激并且后退进为经由肾到的排泄的全身的发行量的胆汁酸和另外的有毒的 cholephils 的分泌物在 hepatocytes 减少他们的保留；到更吸水的、不太有毒的代谢物的恐水病的胆汁酸和另外的有毒的混合物的新陈代谢的刺激；对胆汁的有毒的效果的受伤 cholangiocytes 的保护；apoptosis 的抑制由细胞毒素的胆汁酸的提高的层次引起了；纤维变性的抑制由胆汁酸的漏引起了进仙子胆汁的空间。主要胆汁性肝硬变的 ursodeoxcholic 酸治疗的临床的结果可以被认为是这策略的第一成功。

Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.