On the Mechanisms of Biliary Flux

Abstract

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.

Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

“…In support of the concept of an adaptive response, bile ducts infiltrate into tissue regions with compromised canalicular flux. Recently, imaging techniques have been established that allow the direct flux analysis in bile canaliculi and interlobular bile ducts in intact livers of anaesthetized mice [58,59]. In contrast to the prevailing osmotic concept, these analyses have shown that the transport of solutes in the liquid of bile canaliculi is diffusion dominated, while flow is negligibly small; in contrast, diffusion is augmented by flow in the interlobular ducts [58].…”

“…Recently, imaging techniques have been established that allow the direct flux analysis in bile canaliculi and interlobular bile ducts in intact livers of anaesthetized mice [58,59]. In contrast to the prevailing osmotic concept, these analyses have shown that the transport of solutes in the liquid of bile canaliculi is diffusion dominated, while flow is negligibly small; in contrast, diffusion is augmented by flow in the interlobular ducts [58]. This framework of bile flux becomes relevant to understand under which conditions bile ducts infiltrate into liver tissue.…”

“…Thus, on the background of the novel concept of bile flux (▶ Fig. 3), ductular reactions can be interpreted as an expansion of the flow augmented zone (interlobular bile ducts) to compensate for the compromised diffusion dominated zone (bile canaliculi) [58]. Many damage types may compromise the diffusion dominated zone, including hepatotoxic compounds such as alcohol, obstructive cholestasis, and non-alcoholic steatohepatitis (NASH) [53,58,61].…”

“…3), ductular reactions can be interpreted as an expansion of the flow augmented zone (interlobular bile ducts) to compensate for the compromised diffusion dominated zone (bile canaliculi) [58]. Many damage types may compromise the diffusion dominated zone, including hepatotoxic compounds such as alcohol, obstructive cholestasis, and non-alcoholic steatohepatitis (NASH) [53,58,61]. A typical morphological feature of the damaged diffusion dominated zone is fragmented and/or widened bile canaliculi due to compromised hepatocyte polarity [53].…”

“…Instead, several genes with significant ▶ Fig. 3 The liver lobule consists of the diffusion dominated canalicular zone and the flow augmented network of interlobular ducts [58,59]. When the canalicular network is compromised in chronic liver disease, new ducts infiltrate into the diffusion dominated zone to support the clearance of bile acids.…”