Changes Of Serum Nrf2/HO-1 Levels In Patients With Cholestatic Liver Disease And Their Relationship With Disease And Short-term Response To UDCA Treatment

Backgroud and Objective: Intrahepatic cholestasis(IHC)refers to the pathophysiological process caused by intrahepatic bile acid metabolism and transport disorders,and oxidative stress plays an important role in the continued progression of cholestatic liver disease.Ursodeoxycholic acid(UDCA)is currently the first line of medical treatment for cholestatic liver diseases.The efficacy has been affirmed,but there is still a poor response in patients.Nuclear factorrelated factor 2(Nrf2)acts as a core transcription factor regulating cellular oxidative damage and induces downstream heme oxygenase-1(HO-1)to exert anti-inflammatory and antiinflammatory effects.Oxidation and cytoprotection.Studies have shown that Nrf2/HO-1 is closely related to the development of cholestasis,and there is a potential link with the therapeutic mechanism of UDCA.The aim of this study was to observe the difference in serum Nrf2/HO-1 levels between patients with intrahepatic cholestasis and normal controls;to explore the relationship between changes of Nrf2/HO-1 levels in patients with intrahepatic cholestasis and disease conditions and short-term response to UDCA therapy Sex.To clarify the role of the two in the development of intrahepatic cholestatic liver disease,determine the prognosis of the disease and to provide an early assessment of the UDCA response to provide new ideas.Method: Including 60 patients with newly diagnosed liver disease and 20 healthy controls according to the diagnostic criteria of intrahepatic cholestasis,20 of them were followed up by short-term UDCA.The serum of the above-mentioned subjects was collected for correlation index detection: automatic biochemical analyzer and Roche reagent were used to detect biochemical indexes;ELASA method was used to detect the content of Nrf2/HO-1;thiobarbituric acid method and xanthine were used.The oxidase method was used to detect the contents of MDA and SOD.The analysis of Nrf2/HO-1 changes and clinical biochemical indicators and oxidation should be performed on the basis of analysis of the differences between normal controls and cholestasis,different levels of cholestasis,and levels of Nrf2/HO-1 before and after UDCA treatment.The relevance of the stimulus index;the use of subject characteristics(ROC)curve analysis of Nrf2/HO-1 changes in the judgment of intrahepatic cholestasis and the clinical significance of UDCA short-term response.Result: 1.The content of Nrf2 and HO-1 in patients with internal cholestasis(527.00±168.51 U/L,15.96±4.90 U/L)were significantly higher than those in healthy controls(164.45±34.13 U/L,11.74±2.0 U/L),P<0.001.2.The serum levels of Nrf2 and HO-1 in patients with intrahepatic cholestasis were not significantly different in age,sex,etiology and duration,and there was no correlation with the above factors,P>0.05;Nrf2 in mild(The content of 629.06±171.91 U/L),moderate(533.86±152.19 U/L)and severe(413.37±72.24 U/L)liver damages were significantly different,and the more serious the liver damage was,the higher the level of Nrf2 was the lower,r=-0.485,P<0.001;HO-1 contents were mild(18.02±5.92 U/L)and moderate(14.77±4.02 U/L)and severe(13.86±1.56 U/L),there was a difference between the two groups(P<0.05).Although there was no difference between moderate and severe cases,P>0.05,the levels of them remained declining with the severity of liver injury(r=-0.348,P=0.006),the changes are consistent.3.The change of levels of Nrf2 and HO-1 were negatively correlated with ALT,AST,TBIL,and DBIL in liver injury indicators(Nrf2: r=-0.409,r=-0.459,r=-0.740,r=-0.745,P<0.05;HO-1: r=-0.354,r=-0.441,r=-0.725,r=-0.728,P<0.001);Nrf2/HO-1 level had no correlation with ALP and GGT(P> 0.05),but negatively correlated with TBA(r=-0.574,r=-0.454,P<0.001);MDA decreased with the increase of Nrf2 and HO-1,r=-0.727,r=-0.596,P<0.001;SOD increased with the increase of Nrf2 and HO-1,r=0.830,r=0.723,P<0.001? 4.The area under the ROC curve of Nrf2/HO-1 were 0.936 and 0.785,respectively,and the cut-off points were 0.679 and 0.590 respectively.The susceptibility to the prediction of cholestasis was 92.9% and 75.0%,respectively,and the specificity was 82.1% and 76.9%.5.After treatment with UDCA in patients with intrahepatic cholestasis,the ALT,AST,ALP,GGT,TBIL,DBIL,TBA,and oxidative stress indicators of MDA were significantly lower than before,SOD increased compared with before,P<0.05.Statistical differences: The contents of Nrf2/HO-1 after UDCA treatment were increased by 675.65±129.59 U/L and 19.31±3.70 U/L compared with 551.14±187.78 U/L and 15.91±5.50 U/L before treatment(P<0.05).6.According to the curative effect judgment,according to the UDCA treatment effect is divided into the cure group,the marked effect group and the improvement group.The baseline Nrf2/HO-1 levels in the cured group(627.31±164.34 U/L,16.59±3.97 U/L)were significantly higher than those in the improved group(432.23±64.47 U/L,11.77±2.43 U/L),P<0.05,there are statistical differences.7.The area under the curve of Nrf2 and HO-1 before UDCA treatment was 0.750,0.844,P<0.05,the cutoff point of Nrf2 was 0.542,the sensitivity and specificity were 87.5% and 66.7%,and the cutoff of HO-1 was.The point was 0.625,and the sensitivity and specificity were 87.5% and 75.0 %.After combined treatment of UDCA,the area under the curve of Nrf2 and HO-1 was 0.716 and 0.790,respectively.The cutoff point of Nrf2 was 0.438,and the sensitivity was 81.3%.The specificity was 62.5%;the cut-point of HO-1 was 0.625,the sensitivity was 81.3%,and the specificity was 75.0 %.In conclusion1.The serum level of Nrf2/HO-1 in patients with intrahepatic cholestasis liver disease is significantly increased,and it is negatively correlated with liver injury and cholestasis.The levels of Nrf2/HO-1 may be expected to be used to determine the condition and prognosis of patients with intrahepatic cholestasis.More sensitive indicators.2.The baseline level of serum Nrf2/HO-1 in patients with intrahepatic cholestasis is related to the efficacy of UDCA treatment.The level of change has a certain clinical value in predicting the short-term efficacy of UDCA,but the content of both in the serum changes Whether it is possible to independently evaluate the efficacy of UDCA still needs to be further clarified by the need to increase the sample size and extend the observation period.