Metabolic Signature of Electrosurgical Liver Dissection

Witigo Von Schönfels,Thomas Becker,Gerald Rimbach,Felix Stickel,Sebastian Hinz,Clemens Schafmayer,Oliver Von Kampen,Bence Sipos,Stefan Schreiber,Katharina Balschun,Olga Will,Michael Nothnagel,Patrizia Huebbe,Bodo Schniewind,Christoph Röcken,Jochen Hampe,A Landrock ,Jan–Hendrik Egberts ,K Richter ,E Patsenker ,M Ahrens

doi:10.1371/journal.pone.0072022

Abstract

Background and AimsHigh frequency electrosurgery has a key role in the broadening application of liver surgery. Its molecular signature, i.e. the metabolites evolving from electrocauterization which may inhibit hepatic wound healing, have not been systematically studied.MethodsHuman liver samples were thus obtained during surgery before and after electrosurgical dissection and subjected to a two-stage metabolomic screening experiment (discovery sample: N = 18, replication sample: N = 20) using gas chromatography/mass spectrometry.ResultsIn a set of 208 chemically defined metabolites, electrosurgical dissection lead to a distinct metabolic signature resulting in a separation in the first two dimensions of a principal components analysis. Six metabolites including glycolic acid, azelaic acid, 2-n-pentylfuran, dihydroactinidiolide, 2-butenal and n-pentanal were consistently increased after electrosurgery meeting the discovery (p<2.0×10−4) and the replication thresholds (p<3.5×10−3). Azelaic acid, a lipid peroxidation product from the fragmentation of abundant sn-2 linoleoyl residues, was most abundant and increased 8.1-fold after electrosurgical liver dissection (preplication = 1.6×10−4). The corresponding phospholipid hexadecyl azelaoyl glycerophosphocholine inhibited wound healing and tissue remodelling in scratch- and proliferation assays of hepatic stellate cells and cholangiocytes, and caused apoptosis dose-dependently in vitro, which may explain in part the tissue damage due to electrosurgery.ConclusionHepatic electrosurgery generates a metabolic signature with characteristic lipid peroxidation products. Among these, azelaic acid shows a dose-dependent toxicity in liver cells and inhibits wound healing. These observations potentially pave the way for pharmacological intervention prior liver surgery to modify the metabolic response and prevent postoperative complications.

Highlights

The indications and use of liver surgery have increased substantially over the last decade
Between two and three independent paired liver samples were obtained from six individuals, extracted and subjected to metabolic screening using gas chromatography/mass spectrometry (GC/mass spectrometry (MS))
As an exploratory step to evaluate the global metabolite pattern with regards to the effects of ES, a principal components analysis was performed in the discovery sample set

Summary

Introduction

The indications and use of liver surgery have increased substantially over the last decade. ES preparation induces significant thermic and oxidative damage to the liver. This surgical trauma is associated with a typical decline in liver function during the immediate postoperative period and clearly affects patient survival [6,7] resulting from a loss of liver parenchymal reserve in addition to thermal injury to the remaining parenchyma. Measures to minimize electro surgery-derived tissue trauma could potentially improve postoperative outcomes. To develop such interventions, a better knowledge of the toxic metabolites evolving from ES, and their molecular effects on liver cell regeneration is required. I.e. the metabolites evolving from electrocauterization which may inhibit hepatic wound healing, have not been systematically studied

Methods

Results

Conclusion