What is the pathophysiology of hepatocellular cholestasis?

Updated: Aug 09, 2017
  • Author: Hisham Nazer, MBBCh, FRCP, DTM&H; Chief Editor: Carmen Cuffari, MD  more...
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The mechanisms of cholestasis can be broadly classified into hepatocellular, where an impairment of bile formation occurs, and obstructive, where impedance to bile flow occurs after it is formed. The typical histopathologic features of hepatocellular cholestasis include the presence of bile within hepatocytes and canalicular spaces, in association with generalized cholate injury. Typical of obstructive cholestasis is bile plugging of the interlobular bile ducts, portal expansion, and bile duct proliferation in association with centrilobular cholate injury. [1]

Bile is a highly complex water-based medium containing inorganic ions and many classes of organic amphiphiles, the formation of which involves multiple mechanisms and levels of regulation. The transport of solute into the canaliculus by specific transporters creates chemical and osmotic gradients and promotes water flow by a paracellular pathway. Several of these specific transporters have been identified, and their function has been characterized. The identification of defective transporters in some familial cholestatic disorders has led to improved understanding of the molecular mechanisms of human cholestasis. [2, 3, 4]

Redundancies in the mechanisms of solute transport that result in bile formation are noted. From what is currently known about the process, seemingly few, if any, of the known transporters are absolutely essential in the process. Therefore, the absence or impairment of a single transporter is not expected to result in failure of bile formation. Instead, a process of amplification is required to produce clinical cholestasis. A primary mechanism of amplification is the retention of hydrophobic bile salts, strong detergents that cause membrane injury and impairment of membrane function. Retained bile salts down-regulate new bile acid synthesis, which results in a reduction of the bile salt pool and in reduced enterohepatic recirculation.

Retention of cholesterol results in increased cholesterol content of membranes that reduces their fluidity and impairs the function of integral membrane proteins. These amplification mechanisms result in further retention of damaging substances, accelerated membrane injury and dysfunction, and ultimately, generalized failure of the excretory mechanism for bile. This converging pathway makes the differentiation of cholestatic diseases on clinical grounds very difficult.

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