Hepatic ischemia-reperfusion injury

Hepatic ischemia-reperfusion (I/R) injury is a complex phenomenon occuring in response to interruption of the liver’s blood and oxygen supply and the subsequent restoration of blood flow and tissue oxygenation. Techniques to reduce blood loss and other intra-operative manoeuvers during liver resection can cause hepatic I/R injury. I/R injury to the liver is also unavoidable during the transplantation procedure. This directly impacts liver viability with consequences ranging from mild organ dysfunction to hepatic failure. Hepatic I/R injury has been extensively studied but there is still much to be understood.

Paper I studied the effect of portal triad clamping (PTC) on hepatic metabolism in patients undergoing liver resection using intrahepatic microdialysis to monitor glucose, lactate and pyruvate as markers of ischemia and glycerol as a marker of cell membrane damage. The lactate/pyruvate ratio (L/Pr) was also calculated. PTC induced considerable alterations, with anaerobic metabolism and increased glycogenolysis manifested by increased levels of glucose, lactate and L/Pr and cell membrane damage evidenced by increased levels of glycerol. Papers II and III were methodological studies of hepatic microdialysis in pig models. We could show that microdialysis catheters with membrane cut-off of 20 and 100 kDa could be used equally in hepatic microdialysis for monitoring the products of glucose metabolism and glycerol. However, microdialysis performed using a catheter placed directly in the middle hepatic vein was not equivalent to direct intrahepatic monitoring of the same metabolites. Paper IV investigated the effects of warm I/R injury induced by PTC on hepatic morphology at the ultrastructural level and on the expression of the thioredoxin and glutaredoxin redox systems. On electron microscopy, a significant loss of the liver sinusoidal endothelial cell (LSEC) lining was observed and a decrease of hepatocyte microvilli. Hepatocellular morphology was well preserved apart from the appearance of crystalline mitochondrial inclusions. After reperfusion the LSEC lining showed signs of reactivation. No significant changes were observed in the TRX and GRX redox systems. Paper V explored the value of L/Pr measured by microdialysis as a marker for ischemic complications in 45 patients undergoing liver transplantation (LT). Raised L/Pr defined according to protocol were identified in 24 patients but none were predictive of clinically significant ischemic complications. L/Pr is thus not a reliable marker of clinically significant ischemic events after LT. Paper VI evaluated microdialysis as a postoperative monitoring tool for detection of acute cellular rejection (ACR) in patients undergoing LT. ACR was diagnosed in 33 of 71 transplanted patients. Results revealed metabolic patterns indicating a possible relation between the severity of primary I/R injury and the development of ACR.

In conclusion, warm ischemia induced by PTC causes significant alterations in hepatic metabolism and ultrastructure. L/Pr measured by microdialysis is not a reliable marker for detecting clinically significant ischemic complications early after LT. Primary I/R injury experienced by the organ during the LT procedure may be associated with the development of ACR. It may be possible to monitor larger molecules using microdialysis with 100kDa catheters without affecting the monitoring of small molecules. To get reliable results when monitoring hepatic metabolism by microdialysis the catheter should be placed intrahepatically.

List of scientific papers

I. Isaksson B, D'souza MA, Jersenius U, Ungerstedt J, Lundell L, Permert J, Björnstedt M, Nowak G. Continuous assessment of intrahepatic metabolism by microdialysis during and after portal triad clamping. J Surg Res. 2011 Aug;169(2):214-9.
https://doi.org/10.1016/j.jss.2009.11.720

II. D'souza MA, Ravn A, Jorns C, Nowak G, Isaksson B. Membrane cut-off does not influence results regarding the measurement of small molecules - a comparative study between 20- and 100-kDa catheters in hepatic microdialysis. Clin Physiol Funct Imaging. 2014 Mar;34(2):109-13.
https://doi.org/10.1111/cpf.12071

III. D’Souza MA, von Platen A, Rooyackers O, Nowak G. Hepatic vein microdialysis is not equivalent to intrahepatic microdialysis monitoring for the detection of metabolic changes induced by arterial ischemia in a pig liver model. [Submitted]

IV. Jawad R*, D'souza M*, Selenius LA, Lundgren MW, Danielsson O, Nowak G, Björnstedt M, Isaksson B. Morphological alterations and redox changes associated with hepatic warm ischemia-reperfusion injury. World J Hepatol. 2017 Dec 8;9(34):1261-1269. *Authors contributed equally.
https://doi.org/10.4254/wjh.v9.i34.1261

V. von Platen A, D’Souza MA, Rooyackers O, Nowak G. Evaluation of intrahepatic lactate/pyruvate ratio as a marker for ischemic complications early after liver transplantation - a clinical study. Transplantation Direct. 5(12):e505, December 2019.
https://doi.org/10.1097/TXD.0000000000000952

VI. von Platen A*, D’Souza MA*, Rooyackers O, Nowak G. Intrahepatic microdialysis for monitoring of metabolic markers to detect rejection early after liver transplantation. *Authors contributed equally. [Submitted]