Clinical Analysis Of Intrahepatic Cholestasis During Early Postoperative Period After Liver Transplantation

Although all kinds of traditional Chinese and western medicine treatments were taken, The progress of the end-stage liver disease cannot be contained, not to mention was completely cured.Since Starzl the father of liver transplantation successfully performed the first human liver transplantation in the world in1963, the liver transplantation has got through nearly50years which has became the most effective treatment for patients of end-stage liver diseases. However various postoperative complications impact the long-term survival of receptors and grafts and hyperbilirubinemia is one of the common complications during the early postoperative period after liver transplantation. In recent years,with the continuous improvement of operative technique and the implementation of the preventive measures, the incidence of biliary complications including bile leakage, anastomotic biliary stricture (ABS), nonanastomotic biliary stricture (NABS), biliary infections, biliary calculi, and hemobilia are declined, and intrahepatic cholestasis as an important reason of hyperbilirubinemia during early postoperative period after liver transplantation has received increasing attention. According to the foreign report, the incidence of intrahepatic cholestasis reaches as high as55～90%in the cases of nonselective liver biopsy after liver transplantation, while in China, the incidence of intrahepatic cholestasis is reported to be56%. Despite lots of studies show that the postoperative early transient intrahepatic cholestasis has its special clinical process and most patients recover themselves without the need of special treatments, serious intrahepatic cholestasis is identified with the mortality of receptors and organs. There are various causes of intrahepatic cholestasis according to the relevant domestic and international literatures. It is reported that transient intrahepatic cholestasis is associated with ischemia-reperfusion injury(IRI) and serious intrahepatic cholestasis is caused by the use of suboptimal liver donors, organ preservation injury, poor preoperative clinical status, acute rejection(AR), surgical complication, drug toxicity and postsurgical infection. In order to understand the characteristics of intrahepatic cholestasis during early postoperative period after liver transplantation, we retrospectively analysed225patients who underwent liver transplantation in Nanfang Hospital from August2004to March2011February, so as to find the risk factors associated with serious intrahepatic cholestasis and transient intrahepatic cholestasis during early postoperative period after liver transplantation. These findings can be used to guide the clinical practice.Part I Analysis of serious intrahepatic cholestasis during early postoperative period after liver transplantation[OBJECTIVE]Serious intrahepatic cholestasis is identified with the mortality of receptors and organs. The mechanisms of serious intrahepatic cholestasis include suboptimal liver donors, organ preservation injury, poor preoperative clinical.status, acute rejection(AR),surgical complication, drug toxicity and postsurgical infection. We retrospectively analysed225patients who underwent liver transplantation in Nanfang Hospital from August2004to February2011, so as to study the effect of severe intrahepatic cholestasis on prognosis of patients undergoing orthotopic liver transplantation and identify the risk factors for the occurrence of severe intrahepatic cholestasis.[METHODS]1.Materials Clinical data of patients undergoing orthotopic liver transplantation at Nangfang hospital between August2004and February2011were reviewed retrospectively. Patients with biliary complications, such as biliary stricture, biliary leakage, patients died during the operations or within one week after transplantation or cases without a complete record and patients lost to follow-up were excluded from this study. There were225patients enrolled in this study.2. Diagnostic CriteriaSevere intrahepatic cholestasis during early postoperative period after liver transplantation:Based on the reports of references review severe intrahepatic cholestasis is defined on the basis of a serum bilirubin(TBIL) concentration greater than100umol/L and/or a3-fold increase of alkaline phosphatase(ALP) occurring in the first month after first orthotopic liver transplantation (OLT) and sustained for at least1week, in the absence of biliary complications.3. The choice of relevant factorsForty-one independent variables were selected according to the report of reference literature and the experience in our center.(1)Preoperative factors of receptor: age, gender, primary disease(cirrhosis or not), abdominal surgery history, upper gastrointestinal bleeding history, hepatic encephalopathy, ascites, International Normalized Ratio(INR), prothrombin time (PT), albumin (ALB), total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CR), blood urea nitrogen(BUN), Serum sodium(Na+),Serum potassium(K+), white cell count(WBC), hemoglobin(HB), platelets(PLT), Model for End-Stage Liver Diease (MELD) score and preoperative infection.(2) Factors of donor livers:ABO compatibility, hepatic steatosis, warm ischemic time (WIT) and cold ischemic time (CIT).(3)Intraoperative factors:operation time, operation method, anhepatic phase time, relative warm ischemic time (RWIT), blood loss and blood transfusion(packed red blood cells, plasma, platelets and cryoprecipitate).(4) Postoperative factors:acute rejection(AR), hepatic artery stenosis, hepatic artery thrombosis, bacterial infection(chest, abdominal, bloodstream, urinary and other), fungus infection and cytomegalovirus (CMV) infection.4. Statistical analysisWe divided the patients into two groups (severe intrahepatic cholestasis happened, positive group and severe intrahepatic cholestasis not happened, control group) Firstly, the Forty-one variables were analyzed in univariate analysis to screen out the possible risk factors associated with severe intrahepatic cholestasis during early postoperative period after liver transplantation. Count data were compared by χ2test when meet the condition, otherwise by Fisher’s Exact Test. Measurement data were screened by Kolmogorov-Smirnov normality test. The normal data were compared by independent samples t test, others by independent samples Wilcoxon rank sum test. In view of the existence of certain factors can interact, there will be statistically significant risk factors included in Logistic regression analysis to identify major risk factors. Using SPSS13.0statistical software, according to α=0.05significance level, P<0.05for the difference statistically significant.[RESULTS]1. General resultsA total of225patients (196male and29female) who underwent liver transplantation in Nanfang Hospital from August2004to February2011were included in the analysis.The average age was48.36±11.21(16～75).In respect of operation method, there were167cases of classic orthotopic liver transplantation(COLT) and58cases of piggyback orthotopic liver transplantation (POLT). Hepatitis b surface antigen (HBsAg),Hepatitis c antibody (HCvAb), HIV antibody and treponema antibody of all donor livers were negative. In terms of hepatic steatosis,203cases of no fatty change and22cases of mild steatosis(less than30%). There were28compatible ABO and197identical ABO livers were used. Sixty patients (26.7%%) fulfilled the definition of severe intrahepatic cholestasis during early postoperative period after liver transplantation. There were25deaths in the positive group (41.7%) as opposed to32deaths in the control group(19.4%)in6 months after operation. The mortality rate were significantly different between the two groups (x2=11.539, P<0.01).2. Univariate analysisAfter univariate analysis of41perioperative factors, significant difference was found in27related factors between the positive group and control group statistically: cirrhosis, hepatic encephalopathy, ascites, INR, PT, TBIL, AST, ALB, Na+, K+, Hb, PLT, the use of compatible ABO and mild steatosis livers, WIT, CIT, blood loss, blood transfusion(packed red blood cells, platelets and cryoprecipitate),AR, hepatic artery thrombosis, bacterial infection(chest, bloodstream and other), fungus infection and CMV infection.3. Multivariate analysisAll variables associated with the development of severe intrahepatic cholestasis in the univariate analyses with a significance value of P<0.05were included in a multivariable logistic regression model to identify the factors that were independently associated with the development of this complication. This model identified8independent risk factors associated with severe intrahepatic cholestasis:hepatic artery thrombosis (OR=53.203, P<0.05), TBIL (OR=15.824, P<0.05), mild steatosis livers (OR=7.986, P<0.05), bloodstream infection(OR=4.111, P<0.05), chest infection (OR=3.336, P<0.05), CMV infection(OR=3.215, P<0.05),acute rejection(OR=3.025, P<0.05), cryoprecipitate transfusion (OR=2.878, P<0.05). On the contrary, higher PLT(OR=0.327, P<0.05) and longer PT(OR=0.252, P<0.05) were associated with reduced odds of severe intrahepatic cholestasis.[CONCLUSION]Severe intrahepatic cholestasis during early postoperative period after liver transplantation is associated with increased mortality in6months after operation.Correction of poor clinical statuses before transplantation, avoidance of fatty livers, improvement of surgical technique, reinforce of fight infection and anti-rejection may reduce the complication and decrease the associated early mortality. Part Ⅱ Analysis of transient intrahepatic cholestasis during early postoperative period after liver transplantation[OBJECTIVE]There are various causes of intrahepatic cholestasis and intrahepatic cholestasis as an important reason of hyperbilirubinemia has received increasing attention. A large proportion of intrahepatic cholestasis perform transient clinical symptoms. The reasons of transient intrahepatic cholestasis are really complicates. We retrospectively analysed165patients who underwent liver transplantation in Nanfang Hospital from August2004to February2011, so as to study the effect of transient intrahepatic cholestasis on prognosis of patients undergoing orthotopic liver transplantation and identify the risk factors for the occurrence of transient intrahepatic cholestasis.[METHODS]1.MaterialsClinical data of patients undergoing orthotopic liver transplantation at Nangfang hospital between August2004and February2011were reviewed retrospectively. Patients with biliary complications, such as biliary stricture, biliary leakage, patients with severe intrahepatic cholestasis, patients died during the operations or within one week after transplantation or cases without a complete record and patients lost to follow-up were excluded from this study. There were165patients enrolled in this study.2. Diagnostic Criteria(1)Transient intrahepatic cholestasis during early postoperative period after liver transplantation:Based on the reports of references review transient intrahepatic cholestasis is defined on the basis of hyperbilirubinemia (conjugated bilirubin more then50%) and increase of ALP and/or GGT occurring in the first month after first orthotopic liver transplantation (OLT) in the absence of biliary complications. In the meantime those increases are not reach the diagnostic criteria of severe intrahepatic cholestasis.(2)Hyperbilirubinemia:TBIL is greater than25.6μmmol/L. Synchronously unconjugated bilirubin is greater than17μmmol/L or conjugated bilirubin is greater than5.13μmmol/L.3. The choice of relevant factorsThe same as Part I.4. Statistical analysisWe divided the patients into two groups (transient intrahepatic cholestasis happened, positive group and transient intrahepatic cholestasis not happened, control group) Firstly, the Forty-one variables were analyzed in univariate analysis to screen out the possible risk factors associated with transient intrahepatic cholestasis during early postoperative period after liver transplantation. Count data were compared by χ2test when meet the condition, otherwise by Fisher’s Exact Test. Measurement data were screened by Kolmogorov-Smirnov normality test. The normal data were compared by independent samples t test, others by independent samples Wilcoxon rank sum test. In view of the existence of certain factors can interact, there will be statistically significant risk factors included in Logistic regression analysis to identify major risk factors. Using SPSS13.0statistical software, according to a=0.05significance level, P<0.05for the difference statistically significant.[RESULTS]1. General resultsA total of165patients (145male and20female) who underwent liver transplantation in Nanfang Hospital from August2004to February2011were included in the analysis. The average age was48.22±11.59(16-74).In respect of operation method, there were126cases of classic orthotopic liver transplantation(COLT) and39cases of piggyback orthotopic liver transplantation (POLT). Hepatitis b surface antigen (HBsAg),Hepatitis c antibody (HCvAb), HIV antibody and treponema antibody of all donor livers were negative. In terms of hepatic steatosis,156cases of no fatty change and9cases of mild steatosis (less than 30%). There were16compatible ABO and149identical ABO livers were used. Seventy-seven patients (26.7%%) fulfilled the definition of transient intrahepatic cholestasis during early postoperative period after liver transplantation. There were16deaths in the positive group (41.7%) as opposed to16deaths in the control group(19.4%)in6months after operation. The mortality rate were no significantly different between the two groups (χ2=0.177, P=0.674)2. Univariate analysisAfter univariate analysis of41perioperative factors, significant difference was found in4related factors between the positive group and control group statistically: MELD score, WIT, CIT, RWIT.3. Multivariate analysisAll variables associated with the development of transient intrahepatic cholestasis in the univariate analyses with a significance value of P<0.05were included in a multivariable logistic regression model to identify the factors that were independently associated with the development of this complication. This model identified3independent risk factors associated with transient intrahepatic cholestasis: WIT(OR=8.685, P<0.05), CIT(OR=3.548, P<0.05), RWIT(OR=2.902, P<0.05).[CONCLUSION]Transient intrahepatic cholestasis as a common complication during early postoperative period after liver transplantation does not increase the odds of mortality in6months after operation. The reason of transient intrahepatic cholestasis is ischemia-reperfusion injury. Try to shorten the cold ischemia time, warm ischemia time and relative warm ischemia time may reduce the occurrence of transient intrahepatic cholestasis during early postoperative period after liver transplantation.