Decreased bilirubin transport in the perfused liver of endotoxemic rats

Abstract

Background/Aims: Hyperbilirubinemia associated with sepsis is frequently observed in humans. In this study, an experimental rat model was developed to study bilirubin metabolism and transport during endotoxemia. Methods: Rats were injected intravenously with a single bolus of lipopolysaccharide (1 mg/kg); after 18 hours, the liver was removed for single-pass perfusion. Unconjugated bilirubin, bilirubin ditaurate (125 nmol/ min), and/or taurocholate (1.5 μmol/min) were infused. Rate constants for uptake were determined from the disappearance of a bolus of bilirubin ditaurate in a recirculating perfusion. Results: In endotoxemic livers, biliary excretion of bilirubin-glucuronides was reduced by 49% (2.04 ± 0.2 and 3.99 ± 0.24 nmol·min−1·g liver−1). Similar results were obtained with bilirubin ditaurate, indicating that the reduced transport is not caused by a reduced conjugation capacity. The rate constant of sinusoidal uptake was significantly reduced during endotoxemia (0.191 ± 0.034 vs. 0.090 ± 0.035, respectively). Secretion of taurocholate into bile was also reduced (92 ± 22 vs. 127 ± 10 nmol·min−1·g liver−1). Conclusions: In endotoxemic rats, biliary clearance of bilirubin and taurocholate is substantially decreased, suggesting that decreased output of bilirubin-glucuronides is not caused by impaired conjugation but by a reduction in transport.