Chapter 3 - Mechanisms of bile formation and cholestasis

Summary

Cholestastic disorders comprise a large group of conditions affecting infants and children. Damage to the liver occurs from multiple effects of the various retained biliary constituents, including various lipids, toxins, and bile acids. Therefore impairments in bile flow and secretion – cholestasis – particularly in the infant liver, drive the development and progression of liver disease. With the recent findings of genetic causes of cholestasis (see Chapter 13), many of the previously labeled “indeterminate” or “idiopathic” forms of cholestasis have now been properly assigned to specific impairments in critical genes involved in the formation of bile, including a primary focus on genes for the canalicular transporters [1,2]. In a similar vein, exploration of the effects of various endogenous and exogenous factors on the expression and function of these same essential genes has led to a greater molecular understanding of acquired forms of cholestasis. It is now becoming increasingly possible to assign genetic contributors to both genetic and acquired forms of liver disease. In addition, we have an increased understanding of how these gene products are engaged in the response and adaptation to cholestasis, and, intriguingly, why these processes may not be fully adequate to protect the liver. In particular, see Stapelbroek et al. [1], Mullenbach and Lammert [2], and Karpen and Trauner [3], who discuss our increasing knowledge of the expression, structure, and regulation of these genes and gene products in the underlying processes that lead to cholestasis. It is now accepted that the processes of bile formation, cholestasis, and adaptation are inherently intertwined with structural, developmental, biochemical, intercellular communication, subcellular organization, cell signaling pathways, and physiological components of the liver and liver function. In this chapter, attention will focus upon the basic mechanisms of bile formation, as well as the genetic and acquired pathways that lead to cholestasis.