Beeinflussung des Regenerationsprozesses nach 70 % Leberresektion durch ein postoperatives Galleleck im Rattenmodell

Abstract

Postoperative bile leakage is a typical complication in liver surgery. The influence of bile leakage and concomitant bile peritonitis on the regenerative capacity of the liver remnant has yet not been investigated thoroughly. Methods: SD rats were randomized to the following groups: Sham operation (Sh), 70 % liver resection (LR) and 70 % liver resection with simultaneous induction of a bile leakage (LR+BL) of the right liver lobes. Six rats per group were killed 6, 24, 48 and 96 hours after surgery. Liver regeneration was evaluated by relative liver weight, mitotic index, BrdU labelling index and Ki-67 index. Markers for liver function (thromboplastin time, bilirubin, albumin, ICG disappearance rate) and hepatocellular damage (transaminases, histomorphology) were evaluated as well. In addition, the inflammatory response was determined by measurement of IL-1β, TNF-α, IL-6 mRNA, TGF-β mRNA and myeloperoxidase activity. The bacterial concentration in different organs was quantified by routine microbiologic methods. Results: Liver regeneration was significantly delayed by postoperative bile leakage. After 24 hours, the mitotic index in the LR+BL group (9 ± 6) was significantly reduced compared to the group with LR only (83 ± 20). The relative liver weight (1,42 ± 0,05 %) and the overall-growth fraction (2 ± 1 %), determined by the number of Ki-67-positive cells, were also reduced in the LR+BL group after 24 hours, compared to the LR group (rel. liver weight 1,78 ± 0,04 %, growth fraction 24 ± 2 %). In the LR group regenerative markers declined 48 hours after surgery, whereas the regenerative process reached its maximum in the LR+BL group at that time. For instance, the Ki-67 index was significantly higher 48 h after LR+BL (38 ± 7 %) than after LR alone (21 ±5 %). 96 hours after LR+BL, increased regenerative activity of hepatocytes could still be observed, but the foremost proliferative activity was seen in non-parenchymal cells (as shown by BrdU-positive non-parenchymal cells), especially bile duct epithelial cells. In the LR+BL group, liver function was markedly impaired 24 and 48 hours after surgery, compared to LR only. At early examination times, bile flow was clearly reduced; serum bilirubin was elevated and the ICG disappearance rate was significantly impaired. At no time point, histomorphologic features of liver cell necrosis or significant differences in liver histology were observed in any of the groups. Following LR and BL, the postoperative transcription of cytokines, particularly IL-6, was markedly higher. A significant bacterial super infection in the first 24 hours could be excluded, since microbiologic examination — especially of the liver — revealed no increased bacterial concentrations compared to the LR group. Conclusion: The study shows, that the inflammatory response following intraabdominal bile leakage can promote suppression of liver function as well as impairment of the regenerative capacity of the liver. However, the involved mechanisms remain to be unravelled.

This study was supported by grants from the Deutsche Forschungsgemeinschaft (Se1694/2-1)