Endotoxemia during liver transplantation (2007)

We read with great interest the study by Abdala et al.,1 which examines whether there is significant bacterial translocation during liver transplantation. This is of particular interest because we have recently shown that endotoxin can impair immune function in the context of liver disease, which may have significant ramifications for recovery.2 We would like to congratulate the authors for undertaking such an innovative and difficult study. We would also like to address some points relating these interesting observations to the findings of our own work, possibly providing new insights into the pathophysiological basis of infection in liver dysfunction and recovery from ischemia/reperfusion injury. The authors have shown that portal and/or systemic endotoxemia is found in all patients in their study undergoing liver transplantation and that there is a failure of the liver to clear the endotoxin immediately post liver transplantation.1 Therefore, the question arises of what the clinical effect of this endotoxemia in the context of liver transplantation might be. We have recently shown that endotoxin impairs the function of neutrophil granulocytes by activating them fully; this renders them unresponsive to a further bacterial challenge that is associated with reduced phagocytic capacity. These changes in neutrophil function are associated with increased infection rates, organ failure, and mortality.2 We would like to ask the authors whether they have data on infections and outcome after transplantation and whether there is a relationship between systemic endotoxin load and the rate of infections in the posttransplantation period. The most important finding in the study by Abdala et al.1 in our view is the lack of hepatic clearance of endotoxin shortly after liver transplantation. We however question the conclusion of the authors that hepatic endotoxin clearance might be diminished solely because of an alteration of the reticuloendothelial system. It is well known that endotoxin is also cleared via a hepatocellular mechanism and excreted into the bile.3 Indeed, Kupffer cell depletion has been shown to increase endotoxin clearance.3 It is possible that the Kupffer cells may take up endotoxin and react to it by production of proinflammatory cytokines and that the hepatocytes are the cells that remove endotoxin form circulation. If this hypothesis is correct, one would expect to see the observed endotoxin load increase in the immediate postoperative period as hepatocellular function and bile excretion are known to be impaired following transplantation because of ischemia/reperfusion injury.4 It would be insightful to correlate the degree of ischemia/reperfusion injury with the degree of endotoxemia. Therefore, we would like to ask the authors if they have tried to correlate levels of aminotransferases as a surrogate marker of ischemia/reperfusion injury with endotoxin concentrations during the first days after transplantation. According to the aforementioned hypothesis, the degree of ischemia/reperfusion injury may be related to impairment in hepatic clearance of endotoxin, the highest systemic endotoxin levels being observed in the patients with the highest elevation of aminotransferases after transplantation. Clinical proof for this concept has been provided by the fact that the use of probiotics prior to liver transplantation, which are known to reduce systemic endotoxemia,5 probably by decreasing gut permeability,6 decreases the rate of infection after transplantation.7 As the authors discuss, endotoxemia is likely due to high gut permeability, which is known to be increased in liver disease patients and can be tested noninvasively.8 It would therefore be discriminating to examine if the endotoxemia found in the patients studied is due to increased gut permeability of cirrhosis that is exacerbated by liver transplantation or if it is directly related to the procedure itself. Therefore, we wonder if the authors have data on the gut permeability in the subjects prior to transplantation; such data would provide an important insight into the mechanism of the observations made in their study. Additionally, the serial measurement of systemic endotoxin levels in the first few days after transplantation and the relationship with serum aminotransferases would provide information on the impact of the procedure itself. In conclusion, this study provides important information on endotoxemia and the lack of hepatic endotoxin clearance in the context of liver transplantation. We hope that the authors have access to additional data to help resolve some of the remaining questions, which will possibly provide a better understanding of the interaction between the observed endotoxemia and functional defects in liver function and susceptibility to infection. Vanessa Stadlbauer*, Nathan A. Davies*, Gavin A.K. Wright*, Rajeshwar P. Mookerjee*, Rajiv Jalan [email protected]*, * Liver Failure Group, The Institute of Hepatology, Division of Medicine, University College London, London, United Kingdom.