The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study

Abstract

Post-hepatectomy liver failure (PHLF) remains the major contributor to death after liver resection. Oxidative stress is associated with postoperative complications, but its impact on liver function is unclear. This first in-human, prospective, single-center, observational pilot study evaluated perioperative oxidative stress and PHLF according to the ISGLS (International Study Group for Liver Surgery). Serum 8-isoprostane, 4-hydroxynonenal (4-HNE), total antioxidative capacity, vitamins A and E, and intraoperative, sequential hepatic tissue 4-HNE and UCP2 (uncoupling protein 2) immunohistochemistry (IHC) were assessed. The interaction with known risk factors for PHLF and the predictive potential of oxidative stress markers were analyzed. Overall, 52 patients were included (69.2% major liver resection). Thirteen patients (25%) experienced PHLF, a major factor for 90-day mortality (23% vs. 0%; p = 0.013). Post-resection, pro-oxidative 8-isoprostane significantly increased (p = 0.038), while 4-HNE declined immediately (p < 0.001). Antioxidative markers showed patterns of consumption starting post-resection (p < 0.001). Liver tissue oxidative stress increased stepwise from biopsies taken after laparotomy to post-resection in situ liver and resection specimens (all p < 0.001). Cholangiocarcinoma patients demonstrated significantly higher serum and tissue oxidative stress levels at various timepoints, with consistently higher preoperative values in advanced tumor stages. Combining intraoperative, post-resection 4-HNE serum levels and in situ IHC early predicted PHLF with an AUC of 0.855 (63.6% vs. 0%; p < 0.001). This was also associated with grade B/C PHLF (36.4% vs. 0%; p = 0.021) and 90-day mortality (18.2% vs. 0%; p = 0.036). In conclusion, distinct patterns of perioperative oxidative stress levels occur in patients with liver dysfunction. Combining intraoperative serum and liver tissue markers predicts subsequent PHLF. Cholangiocarcinoma patients demonstrated pronounced systemic and hepatic oxidative stress, with increasing levels in advanced tumor stages, thus representing a worthwhile target for future exploratory and therapeutic studies.

Keywords: liver dysfunction; liver resection; outcome; oxidative stress; post-hepatectomy liver failure.

Figure 1

Dynamics of serum oxidative stress marker levels in the overall cohort (median with interquartile range/IQR). Abbreviations: POD1 and POD5 = postoperative days 1 and 5; * p < 0.05; ** p < 0.001; ns = not significant (Wilcoxon Signed Rank test for paired samples).

Figure 2

Dynamics of serum oxidative stress marker levels stratified by patients experiencing PHLF vs. no PHLF (medians with interquartile range/IQR). Abbreviations: 4-HNE = 4-hydroxynoneal; PHLF = post-hepatectomy liver failure; POD = postoperative day; * p < 0.05; ** p < 0.001; ns = not significant (Mann–Whitney U test).

Figure 3

Predictive value (AUROC; left) of oxidative stress serum markers for development of PHLF after liver resection and event rates of PHLF (middle) and CR-PHLF (right) according to calculated cut-offs stratifying low- vs. high-risk patients (Chi-Square and Fisher’s exact test). 4-HNE = 4-hydroxynonenal; AUC = area under the curve; CI = confidence interval; CR-PHLF = clinically relevant post-hepatectomy liver failure (ISGLS grade B or C); PHLF = post-hepatectomy liver failure; POD = postoperative day.

Figure 4

Liver tissue oxidative stress markers (4-HNE and UPC2) before and after resection (in situ liver) stratified by occurrence of PHLF. Boxplots: median with interquartile range (IQR) and min/max; dots: individual values. 4-HNE = 4-hydroxynonenal; PHLF = post-hepatectomy liver failure; UCP2 = uncoupling protein 2; * p < 0.05; ** p < 0.001; ns = not significant (Mann–Whitney U test).

Figure 5

Predictive value of tissue 4-HNE alone (top panel) or in combination with serum 4-HNE (bottom panel) for PHLF after liver resection (left). Event rates of PHLF (middle) and CR-PHLF (right) according to low- (vs. intermediate) vs. high-risk cut-offs (Chi-Square and Fisher’s exact test). 4-HNE = 4-hydroxynonenal; AUC = area under the curve; CI = confidence interval; CR-PHLF = clinically relevant post-hepatectomy liver failure (ISGLS Grade B or C); PHLF = post-hepatectomy liver failure; POD = postoperative day.

Figure 6

Patient examples with low and high PHLF risk according to combined 4-HNE post-resection in situ biopsy IHC and serum level cut-offs (scale bar on IHC images = 50 µm). 4-HNE = 4-hydroxynonenal; ALPPS = associating liver partition and portal vein ligation for staged hepatectomy; CCC = cholangiocarcinoma; CRLM = colorectal cancer liver metastases; IHC = immunohistochemistry; PHLF = post-hepatectomy liver failure; POD = postoperative day.