On the mechanisms of biliary flux.

On the mechanisms of biliary flux.

Vartak N; Drasdo D; Geisler F; Itoh T; Oude Elferink RPJ; van de Graaf SFJ; Chiang J; Keitel Verena; Trauner M; Jansen P; Hengstler JG

Hepatology

2021

2021-06-23

Since the late 1950s, transport of bile in the liver has been described by the “osmotic concept,” according to which bile flows into the canaliculi toward the ducts, countercurrent to the blood flow in the sinusoids. However, because of the small size of canaliculi, it was so far impossible to observe, let alone to quantify this process. Still, “osmotic canalicular flow” was a sufficient and plausible explanation for the clearance characteristics of a wide variety of choleretic compounds excreted in bile. Imaging techniques have now been established that allow direct flux analysis in bile canaliculi of the intact liver in living organisms. In contrast to the prevailing osmotic concept these analyses strongly suggest that the transport of small molecules in canalicular bile is diffusion dominated, while canalicular flow is negligibly small. In contrast, with the same experimental approach, it could be shown that in the interlobular ducts, diffusion is augmented by flow. Thus, bile canaliculi can be compared to a standing water zone that is connected to a river. The seemingly subtle difference between diffusion and flow is of relevance for therapy of a wide range of liver diseases including cholestasis and NAFLD. Here, we incorporated the latest findings on canalicular solute transport, and align them with extant knowledge to present an integrated and explanatory framework of bile flux that will undoubtedly be refined further in the future.

The mechanism of transport of glandular secretions such as saliva, bile, and exocrine pancreatic juice is fundamental to their role in physiology. Recently, reports from two groups have rekindled the decades-old scientific debate on the mechanisms by which biliary fluid and biliary constituents exit the liver.(1-3) Bile acids (BAs) are secreted by the action of ATP-dependent transporter proteins to reach high concentrations in the liver canalicular network, but what transports them out of the canalicular network, into the bile ducts, and finally out of the liver? Conventional wisdom was in favor of an osmotically driven mechanism according to which the BAs and other solutes, such as glutathione, bilirubin and many other organic anions, secreted by hepatocytes, draw water into the bile canaliculi to create bulk canalicular fluid flow. In sharp contrast, work done by the present authors demonstrated the conspicuous lack of measurable flow in canaliculi.(1) Instead, BAs appear to move by molecular diffusion in a virtually stagnant canalicular fluid until they reach the bile ducts. Only in the ducts is fluid flow evident, caused by local inorganic ion secretion, drawing water from the cholangiocytes into the ductular lumen. Moreover, an osmotic potential generated by the high concentration of solutes diffusing from the canalicular network into the ducts may contribute to water influx from cholangiocytes into the ductular lumen, although this mechanism has not yet been directly proven. Therefore, the ducts, much more than the canaliculi, may represent the anatomical site where bile flow originates. Although this distinction in the anatomical site of origin of bile flow may seem like splitting hairs, it has important consequences for the understanding and development of therapy of various liver diseases. Solving this conundrum requires a multi-disciplinary excursion into fluid mechanics, molecular diffusion, and the development of new techniques that allow direct measurement of these processes in the biliary tract of intact functioning livers. After discussing the fundamental biophysical theory and presenting recently published data in this context, we here present a framework for bile flux and discuss its implications on pathophysiology and therapeutic developments.

Journal Article

NEOMED College of Medicine

Department of Integrative Medical Sciences

Jan to Aug list 2021