Reduction of ischemia reperfusion injury after liver resection and hepatic inflow occlusion by alpha-lipoic acid in humans

Abstract

Aim: To evaluate the protective effects of preconditioning by alpha-lipoic acid (LA) in patients undergoing hepatic resection under inflow occlusion of the liver.

Methods: Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCl 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver.

Results: Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNEL-positive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion.

Conclusion: This is the first report on the potential for LA reducing ischemia/reperfusion injury (IRI) of the liver in humans who were undergoing liver surgery. Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.

Figure 1

Lactate (A) and cholinesterase (B) levels after laparotomy (LAP), 30 min of ischemia (pP0´), 30 min of ischemia with 30 min of reperfusion (pP30´) and 24 h after operation with and without 600 mg LA 15 min prior to ischemia, values as means ± SD, n = 12 each group, ^aP < 0.05 vs NaCl.

Figure 2

AST (A) and ALT (B) levels after laparotomy (LAP), after 30 min of ischemia (pP0´), after 30 min of ischemia with 30 min of reperfusion (pP30´) and after d 1-3 (peak level) with and without 600 mg LA 15 min prior to ischemia, values as means ± SD, n = 12 each group, ^aP < 0.05 vs NaCl.

Figure 3

ATP-content in liver tissue after laparotomy (LAP), after 30 min of ischemia (pP0´) and after 30 min of ischemia with 30 min of reperfusion (pP30´) with and without 600 mg LA 15 min prior to ischemia, values as means ± SD, n = 12 each group, ^aP < 0.05 vs NaCl.

Figure 4

Representative liver sections after laparotomy (LAP), after 30 min of ischemia (pP0') and after 30 min of ischemia with 30 min of reperfusion (pP30') with and without 600 mg LA 15 min prior to ischemia, (HE×200-400). A, B: In both groups no features of cell injury after LAP; C, D: At pP0' there was a mild oncotic injury in the untreated and pretreated group such as hepatocytes swelling and vacuolization; E, F: At pP30' oncotic injury was increased especially in the untreated group (F): there were areas with focal necrosis (asterisk) and areas with eosinophilia and oncosis (arrows). In the LA pretreated group oncotic cell injury was rare (E).

Figure 5

Representative liver sections stained with TUNEL assay after 30 min of ischemia (pP0') and after 30 min of reperfusion (pP30') with and without 600 mg LA 15 min prior to ischemia. Positive control was prepared from liver-tissue samples by treating with DNase I in accordance with manufactures guidelines (E). After LAP TUNEL-positive hepatocytes were rare (data not shown). We observed TUNEL-positive hepatocytes in the untreated group at pP0' and at pP30' (B, D) while TUNEL staining was decreased in the LA pretreated group at the same time point (A, C); F: TUNEL-positive hepatocytes after laparotomy (LAP), after 30 min of ischemia (pP0') and after 30 min of reperfusion (pP30') with and without 600 mg LA 15 min prior to ischemia, values as means ± SD, n = 5 each group, ^bP < 0.01 vs vehicle (NaCl) group.