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Chapter 3 - Mechanisms of Bile Formation and the Pathogenesis of Cholestasis
- from Section I - Pathophysiology of Pediatric Liver Disease
- Edited by Frederick J. Suchy, Ronald J. Sokol, William F. Balistreri
- Edited in association with Jorge A. Bezerra, Cara L. Mack, Benjamin L. Shneider
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- Book:
- Liver Disease in Children
- Published online:
- 19 January 2021
- Print publication:
- 18 March 2021, pp 26-35
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Summary
Bile formation and flow is an essential physiological function. Adequate bile flow is necessary for innumerable daily functions including digestion, metabolism, growth, development, toxin elimination and adaptation to liver disease. Cholestasis, a slowing or, in its extreme form, cessation of bile flow, is a pathophysiological process that interrupts the necessary functions of bile while biliary constituents accumulate intrahepatically [1–3]. This accretion of bile leads to liver damage from the multiple effects of retained biliary constituents, including various lipids, toxins, and as a principal effector – bile acids [4–6]. These effects of cholestasis, regardless of cause, are amplified and accelerated in the infant, rendering the consequences of unaddressed neonatal cholestasis urgent [1, 7–9]. A molecular understanding of the determinants of bile formation is helpful to link these individual solutes to the responsible genes and functions in normal biology and in cholestasis. Bile formation and flow relies upon membrane transporters of biliary solutes, and their regulators, that function to deliver each of the molecular constituents into bile. The focus of this chapter is to lay the groundwork of current knowledge of the mechanisms of bile formation and to explore normal and pathophysiological processes when these mechanisms are impaired. Moreover, very recent work based upon the knowledge of bile formation has led to new therapeutic targeting, with the goal of filling the serious gap in effective anti-cholestatic therapies.
Chapter 3 - Mechanisms of bile formation and cholestasis
- from Section I - Pathophysiology of pediatric liver disease
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- By Nikita A. Gupta, Emory University School of Medicine, and Pediatric Hepatologist, Children’s Healthcare of Atlanta, GA, USA, Saul J. Karpen, Emory University School of Medicine, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Atlanta, GA, USA
- Edited by Frederick J. Suchy, University of Colorado Medical Center, Ronald J. Sokol, University of Colorado Medical Center, William F. Balistreri
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- Book:
- Liver Disease in Children
- Published online:
- 05 March 2014
- Print publication:
- 20 February 2014, pp 24-31
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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.
3 - Mechanisms of Bile Formation and Cholestasis
- from SECTION I - PATHOPHYSIOLOGY OF PEDIATRIC LIVER DISEASE
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- By Saul J. Karpen, M.D., Ph.D., Associate Professor of Pediatrics and Molecular and Cellular Biology, Faculty, Transitional Biology and Molecular Medicine Program, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Director, Texas Children's Liver Center, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Houston, Texas
- Edited by Frederick J. Suchy, Mount Sinai School of Medicine, New York, Ronald J. Sokol, University of Colorado, Denver, William F. Balistreri, University of Cincinnati
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- Book:
- Liver Disease in Children
- Published online:
- 18 December 2009
- Print publication:
- 07 May 2007, pp 28-34
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- Chapter
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Summary
With the recent findings of genetic causes of cholestasis (see Chapter 14), many of the previously ascribed “indeterminate” forms of cholestasis have been assigned molecular forms of causality because of specific impairments in critical genes involved in the formation of bile. In a similar vein, exploration of the effects of various endogenous and exogenous factors on the expression and function of these same essential bile formation genes has led to a greater molecular understanding of acquired forms of cholestasis. Thus, within the past 5–10 years, it has become possible to tease apart not only the means by which the liver is damaged by rare single-gene defects in critical hepatobiliary genes, but also 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 Chapter 14 and recent references [1–6] for our increasing knowledge of the expression, structure, and regulation of these genes and gene products in the underlying processes that lead to cholestasis. Among the more relevant findings has been that the processes of bile formation, cholestasis, and adaptation are inherently intertwined with structural, developmental, biochemical, intercellular communication, subcellular organization, cell signaling pathways, and physiologic components of the liver and liver function. In this chapter, attention focuses upon the basic mechanisms of bile formation as well as the genetic and acquired pathways that lead to cholestasis.