Hepatic excretory function in sepsis: implications from biophotonic analysis of transcellular xenobiotic transport in a rodent model

Abstract

IntroductionHepatobiliary elimination of endo- and xenobiotics is affected by different variables including hepatic perfusion, hepatocellular energy state and functional integrity of transporter proteins, all of which are altered during sepsis. A particular impairment of hepatocellular transport at the canalicular pole resulting in an accumulation of potentially hepatotoxic compounds would have major implications for critical care pharmacology and diagnostics.MethodsHepatic transcellular transport, that is, uptake and hepatobiliary excretion, was studied in a rodent model of severe polymicrobial sepsis by two different biophotonic techniques to obtain insights into the handling of potentially toxic endo- and xenobiotics in sepsis. Direct and indirect in vivo imaging of the liver was performed by intravital multifluorescence microscopy and non-invasive whole-body near-infrared (NIRF) imaging after administration of two different, primarily hepatobiliary excreted xenobiotics, the organic anionic dyes indocyanine green (ICG) and DY635. Subsequent quantitative data analysis enabled assessment of hepatic uptake and fate of these model substrates under conditions of sepsis.ResultsFifteen hours after sepsis induction, animals displayed clinical and laboratory signs of multiple organ dysfunction, including moderate liver injury, cholestasis and an impairment of sinusoidal perfusion. With respect to hepatocellular transport of both dyes, excretion into bile was significantly delayed for both dyes and resulted in net accumulation of potentially cytotoxic xenobiotics in the liver parenchyma (for example, specific dye fluorescence in liver at 30 minutes in sham versus sepsis: ICG: 75% versus 89%; DY635 20% versus 40% of maximum fluorescence; P < 0.05). Transcutaneous assessment of ICG fluorescence by whole body NIRF imaging revealed a significant increase of ICG fluorescence from the 30th minute on in the bowel region of the abdomen in sham but not in septic animals, confirming a sepsis-associated failure of canalicular excretion.ConclusionsHepatocytes accumulate organic anions under conditions of sepsis-associated organ dysfunction. These results have potential implications for monitoring liver function, critical care pharmacology and the understanding of drug-induced liver injury in the critically ill.

The liver in sepsis: shedding light on the cellular basis of hepatocyte dysfunction

“…They have shown previously that hepatocellular transport at the canalicular pole of the hepatocyte is impaired in sepsis, with the result that a spectrum of hepatotoxic materials accumulates within the septic liver. They now extend these important observations [1]. …”

“…A new report by Gonnert and co-workers from the Center for Sepsis Control and Care in Jena Germany, recently appearing in Critical Care , provides important new insight into the nature and mechanisms of hepatocellular dysfunction in sepsis [1]. Since Bywaters first described the phenomenon of jaundice following severe trauma in 1946 [2], liver dysfunction has been considered a prominent feature of the Multiple Organ Dysfunction Syndrome and has been defined predominantly by hyperbilirubinemia and clinical jaundice [3-6].…”

Advances in sepsis-associated liver dysfunction

“…[24] In addition, considering hypoglycemia is a frequent event in liver failure, the close monitoring of blood glucose levels and careful glucose administration are required, and intensive insulin therapy should then be used with caution.…”

Genipin alleviates sepsis‐induced liver injury by restoring autophagy

“…There is a substantial need for an effective therapy that will decrease the morbidity and mortality associated with sepsis. The liver is a critical organ for host survival in response to sepsis through its role in scavenging bacteria and producing inflammatory mediators; however, it might also become damaged in the pathogenesis of sepsis as the result of a dysregulated inflammatory response (Recknagel et al ; Gonnert et al ). Clinical evidence has shown that hepatic dysfunction is an early event in sepsis and is a specific risk factor for poor outcome (Kramer et al ).…”