Monitoring Oxidative Stress In Acute-on-chronic Liver Failure By Advanced Oxidation Protein Products

Background and Aims:Live failure is a common clinical syndrome of serious liver disease, due to massive necrosis of liver cells, serious damage of liver function, the mortality rate is very high. China is a country with higher incidence of viral hepatitis, many patients eventually develop liver failure and even life-threatening. Acute-on-chronic liver failure (ACLF) is a common type of liver failure. Inflammation and neutrophil dysfunction play an important role in the pathogenesis of ACLF, and increased oxidative stress is also involved. Although liver transplantation remains the curative treatment, the artificial support liver system (ASLL) has become another life-saving option in the face of the shortage of donor organs. Plasma exchange (PE) is the most extensive non-biological ASLL treatment, in China. Advanced oxidation protein products (AOPP) are important marker of oxidative damage proteins.51% of AOPP are cleared from the circulation by the liver. There is evidence that AOPP participate in monocyte and neutrophil activation, inducing respiratory bursts and functioning as an inflammatory mediator. This study aimed to investigate whether AOPP levels can monitor oxidative stress of ACLF patients. Furthermore, to study PE treatment whether can eliminate AOPP.Methods:We measured AOPP levels in 50 ACLF patients,30 patients with compensated liver cirrhosis (CR),30 patients with chronic hepatitis B (CHB) and 50 healthy controls by spectrophotometric assay. In addition, AOPP concentrations were also measured before and after PE treatment in ACLF patients. As an apoptosis marker, serum cytokeratin 18 (CK18 M 30) levels were detected by using enzyme-linked immunosorbent assay (ELISA) to investigate the relationship between AOPP and apoptosis in ACLF patients. In the same time, tumor necrosis factor-α(TNF-a) and interleukin-6 (IL-6) were also detected in ACLF patients by using ELISA. Results are expressed as means±standard deviation. Data were analysed using one-way ANOVA for multiple comparisons. Paired or unpaired t-tests were used to detect the differences between measurement datas. x2 test was used for categorical factors. Pearson's correlation was used for the coefficient of correlation. Cut-off values for the identification of non-survivors with ACLF and survivors were determined using the receiver operating characteristic (ROC) analysis. Cox regression models were used for multivariate analysis of outcome predictors. A P<0.05 was considered statistically significant. All analyses were performed using SPSS 13.0 software.Results:(1) Significantly higher AOPP levels were found in patients with ACLF compared to CR, CHB and healthy controls (69.45±29.04μmol/L vs.19.67±7.02μmol/L,26.75±5.21μmol/L and 21.35±6.15μmol/L, respectively;P<0.001). (2) CK18 M 30 levels were obviously increased in subjects with ACLF as compared to CR, CHB and healthy control individuals (731.16±355.31 IU/L vs.262.56±120.29 IU/L,85.98±32.43 IU/L and 99.60±32.98 IU/L, respectively; P<0.001). (3) There was a positive relationship with TBIL (r=0.621, P<0.001), Child-Pugh scores (r=0.717, P<0.001), MELD scores (r=0.597, P<0.001), CK18 M 30(r=0.385, P=0.006) and TNF-a (r=0.429, P=0.002). (4) AOPP levels provided the more reliable predictor of mortality in the ACLF patients when using an AOPP cut-off of 74.21μmol/L (AUROC 0.832) with a sensitivity of 70.6% and a specificity of 84.8%. Multivariate Cox regression analysis showed AOPP and MELD were independent risk factors for prognosis. The risk ratios were 1.030 and 1.201. (5) After the first PE treatment, the level of AOPP dropped to 43.67±20.64μmol/L (P<0.001), and the AOPP level at the end treatment was 34.65±18.14μmol/L (P<0.001). In addition, the first PE led to a significant decrease (37%) in the AOPP levels in all treated patients. (6) Indeed, our analysis found more earlier dynamic change of AOPP than TBIL in ACLF patients.Conclusions:ACLF patients had high AOPP levels, suggesting a high level of oxidative stress existed in ACLF. And AOPP levels were suitable for monitoring dynamic change the levels of oxidative stress in ACLF patients. There was a positive relationship between AOPP and hepatocyte apoptosis. Increased AOPP may serve as an important biological marker of adverse outcome. In addition, PE therapy was effective in reducing AOPP.