OBJECTIVE: To introduce the immune response of CD4~+ T helper lymphocytes (Th) and their cytokines following liver transplantation. DATA SOURCE: A computer-based online search was conducted in Medline from January 1970 to December 2008, Wanfang Database from January 1998 to December 2008, and China Hospital Knowledge Database from January 1998 to December 2008 with the key words of "liver transplantation, rejection, immune Tolerance, T helper lymphocytes, Th1 cells, Th2 cells" in both Chinese and English. DATA SELECTION: Articles about immune response of Th and their cytokines following liver transplantation were included, but reviews and duplicated studies were excluded. MAIN OUTCOME MEASURES: A total of 36 relative articles about immune response of Th and their cytokines following liver transplantation (n=3), immune effect of Th and cytokines on liver transplantation (n=22), and relationship among Th, cytokines, and transplantation immunity (n=11) were included. RESULTS: T helper lymphocyte was of importance to regulate the immune response, with function of supporting body fluid and cellular immune. Th and their cytokines played a very important role in immune tolerance following liver transplantation. The ration of Th1/Th2 was correlated with the immune response following liver transplantation. The increased Th1 secretion might induce rejection of liver tissue. When the ration turned to Th2, the immune tolerance easily occurred. CONCLUSION: Up to now, the theory of relationship between Th1/Th2 ration and transplantation immunity is not used for clinical application. Therefore, how to determine the immune state of organism by detecting and regulating cytokines, adjust Th1/Th2 ration, and induce specific immunologic tolerance of host become hot topics in the future.

Objective To investigate the clinicopathological characteristics of HBV recurrence after liver transplantation. Methods The retrospective analysis of the clinicopathological changes was performed on 17 patients who had HBV recurrence after liver transplantation in our medical department. Results HBV recurrence happened from 4 to 48 months. Twelve of them which were identified to be YMDD mutation switched to entecavir or added adefovir. Three of them receiving chemotherapy when liver cancer recurred switched to entecavir. Two of them with withdrawal of lamivudine were given lamivudine continuously. Liver function returned to the normal level and HBVDNA was ＜ 102 U/ml after anti-hepatitis B virus. The histological changes in the transplanted livers included hepatocellular degeneration, necrosis and apoptosis, portal infiltrations and fibrosis.With time after recurrence, it was easier to see hepatitis B virus replication in liver cells, incidence of acute rejection, increases of liver fibrosis and the formation of fibrous septa, even pseudolobule.Conclusion In native HBV infection livers, fibrosis occurs more early and develops rapidly. The number of virus is closely related to liver necrosis and inflammation. Early discovery and change to quick and effective treatment of anti-hepatitis B virus in time can improve greatly the prognosis of the patients.

BACKGROUND:Prolonged therapy with lamivudine has been associated with tyrosine-methionine-aspartate-aspartate mutation, which results in hepatitis B recurrence. Recently, antiviral agents, such as entecavir, have high efficacy and low resistance rate in hepatitis B-related liver disease. However, the researches on the effect of entecavir in preventing hepatitis B recurrence after liver transplantation are rare. OBJECTIVE:To investigate the effect of entecavir combined with low-dose hepatitis B immunoglobulin in preventing hepatitis B recurrence after liver transplantation. METHODS:The fol ow-up data of 253 patients who had liver transplantation for hepatitis B virus related liver disease were retrospectively analyzed. Al patients received nucleoside analogues therapy formal y before liver transplantation. The effects of entecavir+hepatitis B immunoglobulin and lamivudine+hepatitis B immunoglobulin were compared in al the patients and the patents with hepatitis B recurrence risk factors (positive preoperative HBeAg, DNA-positive hepatitis B virus, hepatoma and tyrosine-methionine-aspartate-aspartate mutation). RESULTS AND CONCLUSION:A total of 253 patients received hepatitis B virus-related liver transplantation, and 29 patients died. There were 202 patients in lamivudine group in which 26 patients were dead and 16 patients had hepatitis B virus recurrence, and the recurrence rate was 7.92%(16/202). However, entecavir group had 51 patients without hepatitis B virus recurrence in which three patients were dead. There were significant differences in the mortality rate and recurrence rate between two groups. Compared with the lamivudine+hepatitis B immunoglobulin, entecavir+hepatitis B immunoglobulin could effectively reduce the recurrence rate of the patients with hepatitis B virus-related risk factors. Hepatitis B immunoglobulin was terminated and nucleoside analogues were modulated when recurrence appeared. Al patients hepatitis B virus DNA were control ed less than 500 IU/mL and liver function returned to normal level. Log-rank test showed that there was no significant difference in the long-term survival rate after timely treatment of hepatitis B virus recurrence. With the prevention of nucleoside analogues combined with hepatitis B immunoglobulin therapy, timely treatment of hepatitis B recurrence has little influence on the prognosis. Entecavir combined with hepatitis B immunoglobulin can effectively prevent the hepatitis B recurrence. For the patients with hepatitis B virus-related risk factors, entecavir combined with hepatitis B immunoglobulin can better reduce the recurrence rate of hepatitis B than lamivudine+hepatitis B immunoglobulin after liver transplantation.

Mammalian reproduction is closely related to their metabolic status. The hypothalamus-pituitary-gonad axis ( HPG axis) is regulated by various metabolic factors. Glucagon-like peptide-1 ( GLP-1) is one of various metabolic factors that not only affect glycemic and metabolic control, but also with many other effects, including affecting HPA axis. The function of GLP-1 is related to the location of glucagon-like peptide-1 receptor ( GLP-1R) distribution. It has been confirmed that GLP-1R is widely distributed in HPG axis. The effects of GLP-1 and GLP-1R agonists on the HPG axis have also attracted much attention. The positive effects of GLP-1 and GLP-1R agonists on the HPG axis indicated it could be the new target for the new treatment for gonadal diseases. The role of GLP-1 and GLP-1R agonists in the central nervous system is reviewed.

ObjectiveTo investigate the risk factors for tumor recurrence and death after liver transplantation in patients with hepatocellular carcinoma (HCC) and their survival. MethodsThe patients with HCC who underwent liver transplantation in The Fifth Medical Center of Chinese PLA General Hospital from January 2005 to February 2019 were enrolled, and according to the presence or absence of HCC recurrence after liver transplantation, they were divided into recurrence group and non-recurrence group. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. Univariate and multivariate Cox proportional-hazards regression model analyses were used to determine the risk factors for HCC recurrence and death after liver transplantation. The Kaplan-Meier method was used for survival analysis, and the receiver operating characteristic (ROC) curve was used to investigate the predictive value of death-related risk factors after liver transplantation. ResultsA total of 391 HCC patients who underwent liver transplantation were enrolled, with a median follow-up time of 2 years, among whom 78(19.95%) experienced HCC recurrence. Preoperative alpha-fetoprotein (AFP) level＞200 ng/ml (recurrence: hazard ratio ［HR］=252, 95% confidence interval ［CI］: 1.58-4.03, P＜0.001; death: HR=2.99, 95%CI: 1.59-5.62, P＜0.001］, total tumor diameter (recurrence: HR=1.20, 95%CI: 1.12-1.28, P＜0.001; death: HR=1.10, 95%CI: 1.02-1.17, P=0.002), and vascular invasion (recurrence: HR=1.15, 95%CI: 1.04-1.26, P=0.016; death: HR=1.10, 95%CI: 1.03-1.18, P=0.004) were independent risk factors for tumor recurrence and death after liver transplantation. The 1-, 5-, and 10-year overall survival rates after liver transplantation were 94.8%, 84.2%, and 83.5%, respectively, and the 1-, 5-, and 10-year disease-free survival rates were 840%, 75.1%, and 75.1%, respectively. AFP, involvement of major blood vessels, body mass index, and total tumor diameter had a certain value in predicting the death of HCC patients with recurrence, with an area under the ROC curve of 0.789 (95% CI: 0.719-0858). ConclusionTumor biological features before transplantation are the key factors for tumor recurrence after transplantation.

Objective:To study the impact of simultaneous ligation of splenic artery on prognosis of patients with severe hypersplenism in liver transplantation.Methods:A retrospective analysis was performed on the clinical data of 206 patients who underwent liver transplantation in the Fifth Medical Center of PLA General Hospital from December 2016 to February 2019. There were 180 males and 26 females, aged (51.0±9.0) years old. Fifty-one patients underwent splenic artery ligation during liver transplantation and they were enrolled into the observation group, and 155 patients without splenic artery ligation were enrolled into the control group. The changes in white blood cells (WBC), platelets, alanine aminotransferase, total bilirubin and serum creatinine as well as the incidence of postoperative complications were compared between the two groups.Results:The platelet count of the observation group was significantly lower than those of the control group before operation and on days 1, 3, 7, 30 and 90 after operation, (all P<0.05). The WBC counts in the observation group were significantly lower than those in the control group before operation and on days 1 and 3 after operation (all P<0.05). However, there were no significant differences in the WBC counts between the two groups on days 5, 7, 30 and 90 after operation (all P>0.05). There were also no significant differences in alanine aminotransferase and total bilirubin indexes between the two groups after surgery (all P>0.05), but the serum creatinine levels in the observation group were significantly lower than those in the control group on days 3, 5, 7 and 30 after surgery (all P<0.05). There were no significant differences in the rates of infection, severe acute rejection, biliary tract complications, arterial/portal thrombosis and mental complications between the two groups (all P>0.05). The rate of renal replacement therapy for acute kidney injury in the observation group (9.8%, 5/55) was significantly higher than that in the control group (1.3%, 2/155) ( P<0.05). Conclusion:Ligation of splenic artery during liver transplantation was safe and it had a significant advantage in the early postoperative recovery of WBC count and creatinine without increasing the incidence of complications in patients with severe hypersplenism.

Objective:To study the risk factors and treatment of portal vein thrombosis (PVT) in patients after liver transplantation.Methods:The clinical data of 290 recipients who underwent liver transplantation at the Department of Hepatology, the Fifth Medical Center of PLA General Hospital from July 2015 to April 2019 were retrospectively analyzed. There were 245 males and 45 females, with a median age of 51(44, 56) years old. The liver transplantation recipients were divided into two groups according to whether PVT occurred or not after operation: the PVT group ( n=16) and the non-PVT group ( n=274). Gender, age and other clinical data of the recipients were compared between the two groups. Outpatient and inpatient follow-up were performed. The risk factors of postoperative PVT were analysed in the liver transplantation recipients. Results:The median follow-up of these 290 liver transplant recipients was 59(42, 73) months, and 16 patients were confirmed to have PVT after operation, with an incidence of 5.5%(16/290). Multivariate logistic regression analysis showed that preoperative PVT ( OR=12.773, 95% CI: 3.887-41.973) was an independent risk factor for PVT after liver transplantation. For the 16 patients with postoperative PVT, 10 were treated with portal vein intervention, and the remaining 6 patients were treated with oral aspirin or rivaroxaban anticoagulation due to mild symptoms. The 3-year survival rate of the PVT group was 93.8% (15/16), while that of the non-PVT group was 90.1% (247/274). There was no significant difference in the 3-year survival rates between the two groups (χ 2<0.01, P=0.969). Conclusions:Preoperative PVT in recipients was an independent risk factor for PVT after liver transplantation. For patients with postoperative PVT, appropriate treatment resulted in good results without affecting the long-term prognosis of these patients.

Objective:To investigate the clinical efficacy of neoadjuvant chemo-hormonal therapy(NCHT)followed by radical prostatectomy(RP) plus extended pelvic lymphadenectomy for very-high-risk locally advanced prostate cancer.Methods:The data of 327 cases of very-high-risk locally advanced prostate cancer treated in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, The Second Hospital of Tianjin Medical University, and The Third Affiliated Hospital of Sun Yat-sen University from December 2014 to July 2019 were retrospectively analyzed. Patients were divided into two groups according to treatment regimens: the RP group (direct RP + extended pelvic lymphadenectomy 4-6 weeks after the biopsy of prostate) and the NCHT group (4-6 cycles of NCHT prior to RP). There were 171 cases in RP group and 156 cases in NCHT group, respectively. In the RP group, the median age was 67 (ranging 44-83)years. The median PSA at diagnosis was 27.24 (ranging 4.55-207.00) ng/ml. Patients’numbers of clinical T 2, T 3a, T 3b, T 4 stage were 13, 85, 57, 16, respectively, and clinical N 1, N 0 stage were 33 and 138, respectively. Patients’numbers of ISUP grade groups of 1, 2, 3, 4, 5 were 5, 35, 41, 51, 39, respectively. In the NCHT group, The median age was 67 years, ranging 46-78 years. The median PSA at diagnosis was 72.09(ranging 4.08-722.95)ng/ml. Patients’ numbers of clinical T 2, T 3a, T 3b, T 4 stage were 11, 47, 58, 40, respectively, and clinical N 1, N 0stage were 76 and 80, respectively. Patients’numbers of ISUP grade groups of 1, 2, 3, 4, 5 were 1, 11, 33, 43, 68, respectively. At baseline, the NCHT group showed higher PSA, higher ISUP grade, and more advanced clinical stage at diagnosis( P<0.05). The PSA, pathological down-staging rate, and positive surgical margin rate as well as the biochemical recurrence free survival(bRFS)were compared between the two groups. Results:After radical prostatectomy, compared with the RP group, the NCHT group had a higher proportion of patients achieving PSA<0.2 ng/ml at 6-week postoperative follow-up ( P<0.001), a higher pathologic tumor stage down-staging rate ( P<0.001), a higher ISUP down-grading rate ( P<0.001), and a lower positive surgical margins rate ( P<0.001). In addition, 10.9% of the NCHT group achieved pT 0 or minimal residual disease in postoperative pathology exams. Eighty-three patients (48.5%) in the RP group and 125 patients (80.1%) in the NCHT group achieved undetectable PSA after surgery and entered further analysis for bRFS, which showed NCHT group had significantly longer bRFS (19.46 months vs. 6.35 months). NCHT significantly reduced the risk for biochemical recurrence in locally advanced prostate cancer patients( HR=0.278, 95% CI 0.198-0.390, P<0.001). Such a reduce in risk for biochemical recurrence was seen in all subgroups( P<0.001). Conclusions:NCHT might improve surgical outcomes as well as bRFS in very-high-risk locally advanced prostate cancer patients.

Objective:To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3).Methods:This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity.Results:Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment.Conclusions:Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.

Objective:To investigate the clinical manifestations, pathological, and gene mutation characteristics of ABCB4 gene variant-associated cholestatic liver disease in adults. Methods:Eight adult cases of ABCB4 gene variant-associated cholestatic liver disease who were hospitalized in the Department of Hepatology, Fifth Medical Center of the People's Liberation Army General Hospital from May 2010 to December 2022 were enrolled in this study. The clinical manifestations, pathological features, gene variant features, and prognostic conditions were analyzed. Patient gene testing and biological information analysis were performed using whole-exome next-generation sequencing. SPSS 19.0 software was used to conduct descriptive analysis. Results:Among the eight adult cases of the ABCB4 gene variant, there were three males and five females, with a median age of onset of 24 (20, 37) years. There were three cases with a compound heterozygous variant in ABCB4, and the clinical phenotypes included two cases of progressive familial intrahepatic cholestasis type 3 and one case of intrahepatic cholestasis of pregnancy overlapping with low-phospholipid-associated cholelithiasis syndrome. There were five cases with a single heterozygous variant in ABCB4, and the clinical phenotypes included two cases of intrahepatic cholestasis of pregnancy overlapping with drug-induced liver injury and three cases of low-phospholipid-associated cholelithiasis syndrome. Imaging of all eight cases showed liver fibrosis, and six cases already had cirrhosis. All patients underwent liver histopathological examination, which mainly showed cholestasis and portal fibrosis in eight cases, small bile duct hyperplasia in seven cases, copper deposition in three cases, and cirrhosis in five cases. ABCB4 screening revealed 11 different mutations, including eight new mutations. The pathogenicity assessment showed that c.2394+82C>T (intron) was a benign mutation, and the rest were deleterious mutations. Ursodeoxycholic acid was the treatment for all patients, with a follow-up time of 7.5 (0.5, 12.7) years. One case died of end-stage liver disease, two cases developed cholestatic cirrhosis, and five cases were in stable condition. Conclusion:The adult ABCB4 gene variant-associated cholestatic liver disease are mostly single heterozygous mutations, the clinical phenotypes are diverse and overlapping, the disease is more severe in those who carried non-functional mutations.