Sepsis-induced liver failure: Molecular mechanisms and functional significance of excretory dysfunction and impact on critical care pharmacology
Acronym: Liver Dysfunction
Principal Investigator: PD Dr. med. Andreas Kortgen
Team: Esther Fröhlich, Jaqueline Fischer
Research Area: D Sepsis related Organ Failure
Project Number: D1.11
Duration: 01.07.2011 bis 30.06.2015
Module: Senior Research Group
The Problem
The liver plays a key role in metabolism, excretion and host response in critically ill patients. Hepatic dysfunction in inflammation and sepsis is an early and regular feature with a profound impact on prognosis. The project aims to unravel molecular mechanisms of excretory hepatic dysfunction with impairment of transport mechanisms on the basolateral and canalicular membrane and the impact on critical care pharmacology.
Results so far
We hypothesized that hepatic dysfunction especially excretory dysfunction occurs early in the course of sepsis. Like ICG, DY635 is eliminated almost exclusively via hepatocytes into bile. However, kinetics of hepatocellular uptake and elimination are much faster. While in sham-operated rats fluorescence over the liver assessed with intravital microscopy decreases from its maximum value to 71±3% after 35 min for ICG, the value for DY635 is 17±4%. In septic rats (PCI model after 15 h) biliary excretion of the dyes is reduced. Fluorescence of DY635 after 35 minutes amounts to 36±6% of the peak value. Total amount of DY635 recovered in bile 1h after intravenous injection decreases from 60 % in sham animals to 34 % in septic animals. Gene expression of hepatocellular basolateral transporters Oatp1, Oatp2, Oatp8 und Ntcp responsible for uptake of endogenous and exogenous substances is significantly down-regulated in septic rats 15 h after induction of sepsis (PCI model) when compared to sham animals. At the canalicular pole of the hepatocyte gene expression of Mrp2, Mdr2 und Bsep is reduced, while Mdr1 is upregulated.
In 46 liver transplant recipients 12h after transplantation assessment of PDRICG was performed, accompanied by measurement of bile ICG concentration over 3h after iv-injection of the dye. In addition, plasma and bile concentrations of bilirubin were measured in the postoperative course. While PDRICG was not different with respect to patient and graft survival, peak ICG concentration and bile/plasma ratio of bilirubin on the first postoperative day were significantly reduced in non survivors and patients with necessity for retransplantation. Patients presenting sepsis and/or multi organ failure in the early postoperative course had significantly reduced values for peak bile ICG concentration and bile/plasma bilirubin ratio.
Contact
Tel.: +49 (0)3641 - 9 32 31 84
Universitätsklinikum Jena
Klinik für Anästhesiologie und Intensivtherapie
Erlanger Allee 101
07747 Jena