Novel insight into mechanisms of cholestatic liver injury - PubMed (original) (raw)

Review

Novel insight into mechanisms of cholestatic liver injury

Benjamin L Woolbright et al. World J Gastroenterol. 2012.

Abstract

Cholestasis results in a buildup of bile acids in serum and in hepatocytes. Early studies into the mechanisms of cholestatic liver injury strongly implicated bile acid-induced apoptosis as the major cause of hepatocellular injury. Recent work has focused both on the role of bile acids in cell signaling as well as the role of sterile inflammation in the pathophysiology. Advances in modern analytical methodology have allowed for more accurate measuring of bile acid concentrations in serum, liver, and bile to very low levels of detection. Interestingly, toxic bile acid levels are seemingly far lower than previously hypothesized. The initial hypothesis has been based largely upon the exposure of μmol/L concentrations of toxic bile acids and bile salts to primary hepatocytes in cell culture, the possibility that in vivo bile acid concentrations may be far lower than the observed in vitro toxicity has far reaching implications in the mechanism of injury. This review will focus on both how different bile acids and different bile acid concentrations can affect hepatocytes during cholestasis, and additionally provide insight into how these data support recent hypotheses that cholestatic liver injury may not occur through direct bile acid-induced apoptosis, but may involve largely inflammatory cell-mediated liver cell necrosis.

Keywords: Apoptosis; Bile acids; Bile duct ligation; Cholestasis; Innate immunity; Necrosis; Neutrophils.

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Figures

Figure 1

Figure 1

Sample liver sections from C57Bl/6 mice illustrating neutrophil accumulation after bile duct ligation. C57BL/6 mice were subjected to bile duct ligation and sacrificed 24 h later. Hematoxylin and eosin (H and E) stained sections showing focal necrosis at 100× and 400× magnification. Sections stained with an anti-neutrophil antibody. Neutrophils are present largely around areas of focal necrosis in this model.

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