Study On The Correlation And Clinical Value Of Leptin And Its Receptor With Hepatocellular Carcinoma Based On Hepatitis B Cirrhosis

Objective:To investigate the correlation between leptin and its receptor and the occurrence of HCC based on hepatitis B cirrhosis and the clinical characteristics of patients with high leptin and leptin receptor expression,to evaluate the role of leptin in HCC based on hepatitis B cirrhosis combined with metabolic factors or MS,and to evaluate the role of leptin receptor high expression in the development of HCC and its influencing factors.Methods:From October 2010 to October 2015,232 untreated HCC patients with hepatitis B cirrhosis in the biosample bank of metabolic syndrome and risk for the evolution from cirrhosis to liver cancer of the First Affiliated Hospital of Xinjiang Medical University were selected(including 95 cases of child-pugh A grade;excluding patients who has incomplete survival data,18 cases were combined with MS and 129cases were not combined with MS),and 186 patients with hepatitis B cirrhosis(including95 patients with child-pugh A liver function,51 patients with child-pugh B liver function and 40 patients with child-pugh C liver function;among 95 patients with child-pugh A liver cirrhosis,49 patients with MAFLD and 46 patients without MAFLD).In the same period,100 patients with chronic hepatitis B treated in the outpatient department of the First Affiliated Hospital of Xinjiang Medical University were selected as the research objects.Relevant data were obtained through questionnaire survey,anthropological index measurement,blood biochemical index and medical records.The serum leptin level of all research objects was measured by ELISA,the expression of leptin receptor in 35 patients with HCC and adjacent tissues after surgery was detected by immunohistochemistry,and a variety of statistical methods were used:1)The clinical and demographic characteristics,blood biochemistry and other related indexes were compared between the groups;2)To comprehensively analyze the risk factors of HCC based on hepatitis B cirrhosis and hepatitis B cirrhosis;3)To analyze the survival rate of HCC and explore whether LP is related to the overall survival rate of HCC,to investigate the correlation and possible pathogenesis between serum leptin level and hepatitis B cirrhosis,hepatitis B cirrhosis combined with MAFLD,HCC based on hepatitis B cirrhosis and HCC based on hepatitis B cirrhosis combined with MS;4)to evaluate the role and influencing factors of high leptin receptor expression in the development of HCC based on hepatitis B cirrhosis;5)Univariate and multivariate survival analyses were performed to analyze whether the changes of leptin and its receptor were correlated with the overall survival rate of HCC.6)Set up nomogram of recurrence and metastasis and ROC test of prediction model.Results:1)(1)There was no significant difference in age,race,gender,education level,BMI,hepatitis B DNA load,history of hypertension,history of diabetes,smoking history,drinking history and TG between Child-Pugh A grade hepatitis B cirrhosis group and chronic hepatitis B control group(P>0.05).There was a significant difference in CHOL,LDL,HDL,ALT,AFP,GLU and leptin levels between groups(P<0.05);(2)Multivariate logistic regression analysis showed that the levels of leptin(P=0.012,OR=0.389,95%CI=0.186～0.812),LDL(P=0.001,OR=0.075,95%CI=0.017～0.342),HDL(P=0.000,OR=0.093,95%CI=0.028～0.307)were significantly lower than those in chronic hepatitis B group,ALT(P=0.000,OR=25.845,95%CI=6.551～101.972)and GLU(P=0.002,OR=6.589,95%CI=2.055～21.127)were risk factors for hepatitis B cirrhosis;(3)according to whether the MAFLD group was combined,there was no significant difference in age,race,gender,education level,hepatitis B virus DNA load,history of hypertension,history of diabetes,smoking history,drinking history,CHOL,LDL,HDL,TG,ALT,GLU level in group Child-Pugh A with hepatitis B cirrhosis(P>0.05).AFP level(P=0.028)and leptin level(P=0.030)were significantly increased in hepatitis B cirrhosis group combined with MAFLD;Pearson correlation analysis showed that AFP was positively correlated with BMI(P=0.038,r=0.223),and leptin was positively correlated with BMI(P=0.045,r=0.210);Multivariate binary logistic regression analysis showed that leptin(P=0.031,OR=2.036)was associated with liver cirrhosis complicated with MAFLD;(4)There was no significant difference in leptin,CHOL,LDL,HDL,TG,ALT and GLU among Child-Pugh A,B and C groups(P>0.05),but there was significant difference in AFP among the three groups(P=0.001).2)(1)Among 418 samples,95 pairs met the matching conditions.The ages of HCC group and liver cirrhosis group were(49.91±9.901)years and(50.32±10.759)years,respectively(P=0.785);The ratio of male to female was 77:18;The proportion of Han,Uygur and Kazak is 92:2:1;HCC group combined with obesity and/or type 2diabetes were 26 cases(27%),18 cases(18.9%),and cirrhosis group combined with obesity and/or 2 type diabetes 47 cases(49%)and 6 cases(6.3%)respectively.The age,gender,ethnic group were well matched,leptin,GLU,hepatitis B virus DNA load,history of hypertension,smoking history and drinking history had no significant difference(P>0.05).BMI(P=0.029),FER(P=0.027),CRP(P=0.011),AFP(P=0.000),and type 2diabetes mellitus(P=0.009)were significantly different.Multivariate binary logistic regression analysis show leptin(P=0.021,OR=1.142,95%CI=1.020～1.278)、CRP(P=0.047,OR=1.028,95%CI=1.000～1.057)、AFP(P=0.000,OR=1.015,95%CI=1.007～1.024),BMI(P=0.035,OR=0.875,95%CI=0.773～0.991);(2)There was no significant difference between the HCC group with MS and the HCC group without MS in age,gender,race,diabetes history,drinking history,Child-Pugh classification,BCLC stage,tumor number,tumor size,distant metastasis,lymph node metastasis,tumor thrombus and mortality(P>0.05).The history of hypertension(P=0.000),BMI(P=0.000),hepatitis B virus DNA load(P=0.006)and GLU(P=0.000)were different.Multivariate logistic regression analysis showed that hyperglycemia was a risk factor for HCC based on hepatitis B cirrhosis with MS(P=0.028,OR=1.260,95%CI=1.025～1.549);The risk of HCC complicated with MS was 30.126times than that of BMI<25(P=0.000,OR=30.126);The risk of HCC complicated with MS in patients with hypertension was 31.815 times higher than that without hypertension(P=0.000,OR=31.815).Rstudio was used to draw the restricted cubic spline,RMS was used for analysis,and the model was nonlinear tested and fitted with the cut-off point value.Leptin nonlinear relationship test(P=0.084),the association between leptin and HCC combined with MS was not statistically significant(P=0.213),Glu nonlinear relationship test P=0.041,and the association between GLU and HCC combined with MS was statistically significant(P=0.007),When OR=1,the cut-off value of blood glucose is5.025,which is the cut-off value of risk occurrence;(3)Univariate Kaplan Meier survival analysis showed that there were differences between the two groups(P=0.007)with MS(P=0.011),with drinking history(P=0.041),lymph node metastasis(P=0.047)and cancer thrombus;(4)Multivariate Cox survival analysis showed that cancer thrombus(P=0.005,HR=2.372)were the risk factors of HCC.3)(1)There was a statistically significant difference in Ob-R expression between HCC and adjacent HCC tissues,which was higher in cancer tissues than in adjacent cancer tissues(P=0.032).The expression of Ob-R was higher in HCC patients with BMI≥25Kg/m~2(P=0.006),and the expression of Ob-R was higher in HCC patients with hypertension history(P=0.006).There was no significant difference in the expression of blood glucose,AFP and ferritin among different Ob-R groups(P>0.05).Multivariate logistic regression analysis showed that history of hypertension had a statistically significant effect on Ob-R expression(P=0.033),and hypertension would lead to an increased risk of Ob-R overexpression(OR=7.500).The effect of BMI on Ob-R expression was statistically significant(P=0.013),and the increase of BMI would lead to an increased risk of Ob-R overexpression(OR=18.000).(2)Univariate Kaplan-Meier survival analysis showed that different differentiation degree,history of hypertension,history of diabetes and lymph node metastasis had statistically significant differences in the survival rate of patients(P=0.012,P=0.011,P=0.001,P=0.012).Multivariate COX regression analysis showed that moderate and low differentiation of HCC had a statistically significant impact on survival outcome(P=0.011,P=0.035),and the risk of death was increased in moderate and low differentiation group(HR=10.214,HR=6.333).The effect of diabetes on survival outcome was statistically significant(P=0.001),and the risk of death was increased in diabetic population(HR=7.261).The impact of BMI≥25Kg/m~2on survival outcome was statistically significant(P=0.002),and the risk of death was increased in people with BMI≥25Kg/m~2(HR=5.673).The impact of lymph node metastasis on survival outcome was statistically significant(P=0.019),and the risk of death was increased in people with lymph node metastasis(HR=3.390).(3)By establishing the prediction model of Ob-R influencing factors,we can predict the probability value of whether Ob-R is highly expressed from the changes of independent variables such as hypertension history and BMI,and establish the prediction model of multi-factor survival analysis.The probability of HCC death after hepatitis B cirrhosis can be predicted by the changes of independent variables such as degree of differentiation,history of hypertension,history of diabetes,BMI,lymph node metastasis.Conclusion:Serum leptin level in patients with hepatitis B cirrhosis is related to metabolic factors,and is an independent risk factor for HCC development based on hepatitis B cirrhosis.It is also a potential serum factor for evaluating the involvement of obesity in HCC development based on hepatitis B cirrhosis,and has nothing to do with the degree of cirrhosis.Through univariate and multivariate statistical analysis of HCC patients with hepatitis B cirrhosis complicated with MS for the first time,no statistical significance was found between leptin and HCC patients complicated with MS,and no effect of leptin on OS of HCC patients with hepatitis B cirrhosis was found.The analysis of leptin receptor expression in HCC and paracancer tissues based on hepatitis B cirrhosis suggests that the control of metabolic factors such as hypertension,diabetes,and BMI can improve the prognosis of HCC based on hepatitis B cirrhosis.By establishing the prediction model of Ob-R influencing factors,the probability value of whether Ob-R is highly expressed can be predicted from the changes of independent variables such as history of hypertension and BMI,and the prediction model of multi-factor survival analysis can be established.The probability of HCC death after hepatitis B cirrhosis can be predicted by the changes of independent variables such as degree of differentiation,history of hypertension,history of diabetes,BMI,lymph node metastasis,etc.,which has certain guiding significance for clinical prognosis research.