| Background Acute-on-chronic liver failure(ACLF) is a unique liver disease syndrome with dangerous illness,very poor prognoses and high short-term mortality rate. The basis of ACLF is the preexisting chronic liver disease. In western countries,the main etiology of ACLF is HCV infection or alcohol consumption,while in our country and other Asian countries, the commonest cause of ACLF is hepatitis B. ALCF onset nasty, and the progression is relatively faster than common chronic hepatitis, but not as fast as acute liver failure(ALF) which is no basis of chronic liver disease, So ACLF from onset to achieve liver failure has a period of time window, called “acute-on-chronic pre-liver failure(pre-ACLF)”. Although numerous studies have devoted to analysis of the changes of routine indicators of pre- ACLF patients to guide the clinical diagnosis and early warning liver failure. Currently,there still has not formed a widely recognised diagnostic criteria for pre – ACLF in academia. The existence of early warning effedtiveness of the existing indicators have not to be verified yet,still need to explore. So, it is imperative to discover new specific indicators to guide the diagnosis and treatment for pre-ACLF. Hepatocyte apoptosis and necrosis plays a fundamental role in liver failure severity, it is observed that serum levels of cytokeratin-18(CK18) M30 and M65 are sensitive indicators for the necrosis and apoptosis of hepatocytes.So,detecting the levels of serum M65 and M30 may have important significance in early identification and treatment of pre-ACLF.Objective To explore early warning value about the trend of changes of the levels of M65 and M30 in pre-ACLF patients, and the clinical significance in early identification and treatment of pre-ACLF.Methods Serum M30,M65 levels were measured by ELISA in 35 patients with pre-ACLF(20 cases with remission and 15 cases with exacerbations), 40 ACLF patients(20 cases with response to treatment and 20 cases without response to treatment), 20 CHBpatients and 20 health adults; compared the above indicators among the six groups; furthmore, comparascope indicators include biochemical parameters, prothrombin activities(PTA) in the same period. In addition, the 35 patients with pre-ACLF were divided into remission and exacerbations two groups by clinical symptoms,biochemical parameters and PTA. Observed dynamic changes of above comparascope indicators during the treatment.Results1.The serum M30 and M65 levels of pre-ACLF exacerbations patients were as follows:(493.80±143.85)U/L、(712.47±305.67)U/L,they were significantly higher than those of remission(351.40±127.78)U/L 、( 448.15±165.14) U/L( p1= 0.047, p2= 0.039).But the difference of leves of alanine aminotransferase(ALT)(1139.88±1087.26 U/L)、(555.11±394.09)U/L, aspartate aminotransferase(AST)(603.00± 791.17)U/L、(369.58±342.65)U/L,total bilirubin(TB)(133.91±48.20U/L、(117.16 ±38.51)umol/L,PTA(44.65±3.57)%、(46.82±2.61)% were not statistically significant between the two groups(p>0.05).2.The cases with ACLF without response to treatmen( 506.65±166.24) U/L、(769.67±274.42U/L were higher than those of the cases with response to treatment(499.94±205.32)U/L、(724.32±281.17) U/L in serum M30 and M65 levels,but no significant differences were seen between the two groups(p1=0.937,p2=0.719).3.The serum M30 and M65 levels in patients of health adults were significantly lower than any other groups(p<0.05)except CHB group;But there were no significant difference between pre-ACLF exacerbations patients and ACLF patients(p>0.05); The serum M30 and M65 levels in pre-ACLF remission group had no significantly difference with CHB group[( 219.16±155.13)U/L, p1= 0.054、(379.63±318.65)U/L, p2=0.637],but they had statistically significant with ACLF group(p<0.05).4.When the 15 patients in pre-ACLF developtmented to liver failure, their serum M30 and M65 levels were as follows:(572.62±174.86)U/L、(772.18± 260.98U/L, higher than previous(493.80±143.85)U/L、(712.47±305.67)U/L,but the difference had no statistically significant( P1 =0.160,P2=0.063).The serum M30 and M65 levels after the treatment in pre-ACLF remission group(230.15±154.69)U/L、(289.27±206.34)U/Lwere significantly hepatocytes.3. Elevated serum M30 and M65 levels in patients of pre-ACLF at admission is an independent risk factor during the process of pre-ACLF developmenting to liver failure(OR>1).Based on the AUCs of ROC curve, M30、M65 may be more sensitive than ALT et al. for identifying liver injury. According to the coordinates of the ROC curve for the Yorden index, the risk of liver failure was significantly higher in pre-ACLF when M30≥453.70 U/L、M65≥626.71 U/L.4. The levels of M30,M65 in pre-ACLF had significant positive correlation with ALT at admission, they could upward gradually with the worsen of pre-ACLF,.and could gradual downward trend with the better of the disease,while ALT couldn’t. It demonstrated that the levels of M30,M65 were the sensitive indicator of necrosis and apoptosis of hepatocytes, and were strongly associated with the staging and severity of pre-ACLF.while measurement of serum ALT was a sensitive indicator of hepatic injury,but it was apt to be influenced by drug and other factors,so it couldn’t reflect the staging and severity of the disease. lower than that before treatment [(351.40±127.78)U/L]、(448.15±165.14)U/L(P1 =0.035,P2=0.015).5. Correlation analysis of the levels of M30、M65 and serum ALT in pre-ACLF exacerbations group, M30 had significant positive correlation with ALT(r=0.617,P <0.05), M65 had significant positive correlation with ALT( r=0.516,P <0.05), and M30 had significant positive correlation with M65(r =0.828, P <0.01). Correlation analysis of the levels of M30、M65 and serum ALT in pre-ACLF remission group, M30 had significant positive correlation with ALT(r=0.743,P<0.01), M65 had significant positive correlation with ALT( r=0.568,P<0.05), and M30 had significant positive correlation with M65(r =0.724, P <0.01). In the ACLF patients,the serum level of M30 was positively correlated with that of M65(r =0.843, P <0.01), but M30,M65 had non-significant correlation with ALT(r1 =0.135, P =0.571,r2 =0.388, P2=0.091).6. Logistic regression analysis showed that serum M30、M65 level were risk factors for pre-ACLF development to liver failure(OR1= 1.133 P < 0.01, OR2= 1.092 P < 0.05), after adjusting for gender,age,ALT, AST,TB,PTA and ALB. The AUCs of ROC curve in differential diagnosis between remission and exacerbations of pre- liver failure were: M30 0.877, M65 0.867.95%, CI: M30 0.775~0.998, M65 0.741~0.992. while the AUC of ALT、AST、TB、PTA were as follows: 0.545、0.560、0.667、0.450.Conclusion1.The serum M30 and M65 levels in patients of pre-ACLF were significantly increased. It indicated that both remission and exacerbations in pre-ACLF had severe hepatocyte apoptosis and necrosis,and the latter is more serious.They can be differentiated by testing the levels of M30 and M65.2.The serum M30 and M65 levels were not statistically significant between pre-ACLF exacerbations patients and ACLF patients,and there were no statistically significant between pre-ACLF remission patients and CHB patients too. It indicated that they have essential difference in necrosis and apoptosis level of liver cell,and the detection of M30, M65 levels can be used to predict the risk rate of liver failure. The serum M30 and M65 levels in patients of pre-ACLF were significantly higher than that of health adults, It indicated that they are the sensitive indicators for the necrosis and apoptosis of... |
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