Banff classification and progress on liver allograft pathology / 器官移植

The pathology of liver allograft biopsy is not only essential for the evaluation of liver donor, but also for the diagnosis and differential diagnosis of posttransplantation complications. With the development of liver transplantation in clinical practice, relevant studies of the pathological diagnosis of liver allograft complications have been deepened. Banff classification on liver allograft pathology have been gradually established within the international community. In China, pathological studies related to liver allograft pathology have been steadily carried out, and the pathological diagnostic basis of liver allograft pathology suitable for the clinical practice of liver transplantation in China has been gradually formed. This article reviews the history of Banff liver allograft pathology and major pathological lesions of liver allograft complications, aiming to provide reference for implementing pathological diagnosis of liver allograft pathology in China, assisting clinical diagnosis and targeted treatment of complications after liver transplantation, and further improving the survival of liver allograft and recipients.

Advances on researches of clinical pathology and pathogenesis in patients with acute alcoholic hepatitis / 中国中西医结合急救杂志

Alcoholic hepatitis (AH) is an acute severe decompensated alcoholic liver disease (ALD), commonly occurring in heavy drinkers. The pathogenesis of AH is still not fully understood, which may be related to the interactions of multiple complex factors such as alcohol metabolism, inflammation and heredity, etc. Under the background of continuous alcoholic exposure, the pathological changes include hepatocyte steatosis, liver inflammation and fibrosis occurring in the body. This paper summarizes the recent research literatures related to the clinicopathological features, pathogenesis and prognosis evaluation of ALD to comprehensively understand the pathogenesis and pathophysiological characteristics of AH in order to provide theoretical basis for clinical diagnosis and treatment of this disease.

A twenty-year review of clinical liver transplantation / 中华危重病急救医学

Objective To review the development of adult and pediatric liver transplantation in Tianjin First Center Hospital, and to enhance academic exchanges, improve technological innovation, and jointly promote the progress and maturity in the field of liver transplantation. Methods The development of liver transplantation in Tianjin First Center Hospital was analyzed. The clinical data of adult and pediatric liver transplantation from September 1998 to September 2018 were collected. The important events and technological innovation achievements of liver transplantation during the 20 years were summarized. Results The first clinical liver transplantation was attempted in Tianjin First Central Hospital in April 1980. The first long-term survival adult liver transplantation in China was completed in 1994 (11 years survival after the operation). The specialized team of liver transplantation was formally established in September 1998. The 20-year clinical exploration and progress reflected the characteristics of era changes and technological innovation during the rapid development of liver transplantation in China. Our center performed liver re-transplantation in January 1999, reduced-size pediatric liver transplantation in August 2000. In May 2001, we organized the formulation for the preventive and treatment plan for hepatitis B recurrence after liver transplantation. We performed combined liver and kidney transplantation in July 2002, split liver transplantation (SLT) in April 2004, the first domino liver transplantation (DLT) in August 2005. Pediatric living donor liver transplantation (LDLT) was initiated in October 2006, adult LDLT was carried out in August 2007. In September 2007, the first living donor combined liver and kidney transplantation from the same donor in Asia was performed. The first domino+living donor double grafts liver transplantation in the world was performed in January 2009. In March 2011, we performed laparoscopically assisted right hepatic lobe liver transplantation (LDLT) with middle hepatic vein. In May 2014, living donor laparoscopic left lateral lobe procurement was successfully established. In April 2016, simultaneous liver, pancreas and kidney multi-organ transplantation was completed. Domino donor-auxiliary liver transplantation was performed in February 2017. In December 2017, extracorporeal membrane oxygenation (ECMO)-supported liver transplantation in a patient with severe pulmonary hypertension was successfully completed. Liver transplantation combined with partial splenectomy was established in April 2018. Cross-domino liver transplantation (hypersensitive kidney transplantation with auxiliary liver transplantation+pediatric liver transplantation) was performed in May 2018. During the 20 years, the team has performed or assisted other centers in Beijing, Shanghai, Guangzhou and Shenzhen to carry out more than 10 000 cases of liver transplantations. A total of 7 043 cases of various types of liver transplantation were performed in the single center of the hospital (6 005 adult liver transplantations and 1 038 pediatric liver transplantations). Concerning adult liver transplantation, the cumulative 1-year, 3-year and 5-year survival rate from September 1998 to March 2003 were 83.1%, 73.0% and 69.0%, from April 2003 to March 2009 were 85.3%, 76.2% and 72.1% and from April 2009 to September 2018 were 87.5%, 79.2% and 75.1%, respectively. The cumulative 1-year, 3-year and 5-year survival rate for pediatric liver transplantation were 93.5%, 92.2% and 90.2%, respectively. The nucleoside (acid) analogue combined with low dose hepatitis B immunoglobulin (HBIG) was developed to prevent the recurrence of hepatitis B after liver transplantation, this plan has reduced the recurrence rate of hepatitis B and the 5-year re-infection rate of hepatitis B virus (HBV) after liver transplantation significantly. The risk assessment system for tumor recurrence after liver transplantation was established and individual treatment method was established based on this assessment system. Continuous exploration and improvement of liver transplantation for liver cancer, liver re-transplantation, liver transplantation with portal vein thrombosis, SLT, DLT and multi-organ combined transplantation have significantly improved the clinical efficacy of patients and the post-operative survival rate. Conclusions The liver transplantation team of Tianjin First Center Hospital has carried out a scientific and technological exploration on the key problems and technical difficulties of clinical liver transplantation. This work strongly has initiated and promoted the rapid development of liver transplantation in China. The restrictive barrier of hepatitis B recurrence after liver transplantation has been overcome. The risk prevention and control system of tumor recurrence after liver transplantation has been established. A series of innovative achievements that can be popularized have been achieved in the field of complex liver transplantation and expansion of donor liver source. The iterative progress and sustainable development of liver transplantation have been realized.

Changes of inflammatory cytokines in rat liver transplantation model under different functional warm ischemic durations / 中华器官移植杂志

Objective To explore the changes and significance of hepatic cytokines during ischemia and reperfusion in rats undergoing donation after circulatory death (DCD) liver transplantation in different functional warm ischemic durations.Methods Maastricht Ⅲ DCD liver transplantation was simulated and a rat model of functional warm ischemia established.DCD liver transplantation was established by cutting diaphragm.There were four groups of functional warm ischemia 0/15/30 min and living donor liver transplantation control.Liver tissues and serum samples were obtained after donor liver acquisition and 6-hour reperfusion respectively.Luminex liquid chip was employed for detecting the concentrations of 23 cytokines in liver tissue,superoxide dismutase or malondialdehyde (SOD/MDA) expression in liver tissue and alanine transaminase or aspartate aminotransferase (ALT/AST) expression in sera.And hematoxylin-eosin (HE) staining was utilized for detecting liver tissue damage.Results The levels of cytokines in liver tissues during ischemia and reperfusion were significantly different in different functional warm ischemic durations.SOD/MDA in liver tissue,AST/ALT in sera and pathological examinations also showed that,with the prolongation of functional warm ischemic duration,the degree of liver tissue injury gradually aggravated.Conclusions Functional warm ischemic duration has a significant effect on cytokines during ischemia and reperfusion in rat DCD liver transplantation.This phenomenon can help us further elucidate the mechanism of ischemia-reperfusion injury and provide new ideas for preventing ischemia-reperfusion injury during DCD liver transplantation.

Clinicopathological features analysis of common complications in pediatric liver transplantation / 中华器官移植杂志

Objective The purpose of this study was to explore common complications and their clinicopathological features in pediatric liver transplantation.Methods Clinical and pathological data of 240 liver biopsies from 168 children that conducted liver puncture from January 2015 to May 2018 in Tianjin First Central Hospital was retrospectively analyzed.We comprehensively analyzed incidence rate and pathological features of various complications,and correlations between acute rejection and C4d staining result or Banff score.Results A total of 86.67％ (208/240) liver biopsies could be definitely diagnosed with incidence rate of main complications in descending order as follows:T cell mediated rejection (TCMR) 60.57％ (126/208),drug-induced liver injury (DILI) 17.31％ (36/208),biliary complication 8.17％ (17/208),vascular complication 3.37％ (7/208),ischemia/reperfusion injury (IRI) 2.88％ (6/208),antibody mediated acute rejection (AMR) 1.92％ (4/208),HBV infection 1.92％ (4/208),non-alcoholic fatty liver disease (NAFLD) 1.44％ (3/208),chronic rejection (CR) 0.96 ％ (2/208) and HCV infection 0.48 ％ (1/208).TCMR and AMR in acute rejection (AR) accounted for 96.92％ (126/130) and 3.08％ (4/160),and into(portal-based,PB)type TCMR accounted for 96.03％(121/126) with the detectable rate of BP type subtype TCMR of 26.45％(32/121)within 30 d.There were 65.87％ (83/126)、25.40％ (32/126) 和4.76％ (6/126) of BP TCMR samples with "Banff ACR RAI" score within 3-5,6-7 and 8-9,and RAI score was negatively correlated with postoperative time (r =0.127,P =0.084).The incidence rate of central perivenulitis (CP) and portal eosinophils infiltration (PEI) in BP TCMR was 63.63％ (77/121) 和43.80％ (53/ 121),respectively,additionally,the PEI level was positively correlate with RAI score (P＜0.05).CP TCMR and AMR occurred within 30d-365 d and 8 d-180 d,respectively postoperative,while,the two CR occurred at 1095 d and 1335 d postoperative,and significant correlation was strikingly observed between rejection subtype and postoperative time (Z =9.231,P =0.026).C4d positive rate was 10％ (24/240),which was associated with Banff score and postoperative time,besides,C4d score was also correlated with rejection subtype and RAI score.The occurrence of DILI was mainly at time of ＜90 d or ＞180 d postoperative,and the detectable rate of biliary complication within 180 d postoperative was 82.35％ (14/17),IRI Appear in ＜30d.Hepatic artery complication account for nearly 57.14％ (4/7),occurrence time is ≤90 d.Occurrence of HBV infection,CMV infection and NAFLD were mainly at ＞365 d,＜90 d and ＜365 d,respectively.Conclusion There were lots of differences in clinical and pathological features among multi pediatric liver transplantation complications.Liver puncture plays an important role in rejection subtype classification and grading,as well as in non-rejection complications identification.

Experimental study on portal vein ligation combined with in situ splitting on liver regeneration in rats / 中华肝胆外科杂志

Objective To investigate the effect of portal vein ligation combined with in situ splitting on liver regeneration in rats .Methods Seventy-five healthy male Sprague-Dawley rats were selected and randomly assigned into sham operation group ( S) , portal vein ligation group ( PVL) and portal vein ligation combined with in situ splitting group ( ALPPS) .On 1 d, 3 d, 7 d, 10 d, 14 d after operation , the hepatic regeneration rate ( HRR) of right median lobe was calculated , the serum alanine aminotransferase ( ALT) , aspartate aminotransferase (AST), IL-6, HGF, VEGF were detected.mRNA of IL-6, HGF, TNF-α, TGF-βwas assayed by real-time PCR, and the hepatic proliferating cell nuclear antigen ( PCNA) labeling index was evaluated by immunohistochemistry .Results Comparing with PVL group , the HRR of the right median lobe obviously increased on day 3, 7, 10 and 14 in ALPPS group (P<0.05), and ALT and AST level were increased on 1 d (P<0.05).On day 1 and 3, the content of serum IL-6, HGF and VEGF were all in-creased in ALPPS group [(70.7 ±14.6) pg/ml vs.(134.2 ±31.4) pg/ml; (0.70 ±0.04) ng/ml vs. (0.74 ±0.02) ng/ml;(82.1 ±12.6) pg/ml vs.(103.5 ±14.7) pg/ml], respectively (P<0.05).The mRNA expression of IL-6, HGF, TNF-α, TGF-βand the PCNA labeling index were also increased in ALPPS group in comparison with those in PVL group on day 1 and 3 (P<0.05).All the indexes in the two groups were all higher than those in the group S ( P<0 .05 ) .Conclusions Portal vein ligation combined with in situ splitting could significantly enhance liver regeneration .The possible mechanisms were related to the inflammation reaction and stress response caused by in situ splitting and up-regulation of cytokines in the regenerating lobe after portal vein ligation combined with in situ splitting , especially IL-6, HGF and TNF-α.

The impact of mild donor liver steatosis on liver function recovery / 中华器官移植杂志

Objective To investigate the characteristics of liver function recovery in steatotic liver graft transplantations.Method From August 1st 2013 to July 20th 2014,a prospective clinical cohort study of liver transplantations was performed in Tianjin First Central Hospital.Multiple linear regression analyses were made for related factors with the degree of donor liver steatosis and the average total bilirubin (TBil) levels on the post-operative day 6 to 8,week 4,and month 3 and 6,respectively.Result Of 82 cases used for analysis,there were 28 cases of mild steatotic grafts and 54 cases of non steatotic grafts.The multiple linear regression analysis revealed the average TBil level on the post-operative day 6 to 8 was the only one index related with the degree of graft steatosis.By the same means,recipient age,the aspartate aminotransferase (AST) level on the post-operative day 1,the average AST level on the post-operative day 2 to 3,and the degree of graft steatosis were associated with the average TBil level on the post-operative day 6 to 8.The AST level on the postoperative day 1,the average AST level on the post-operative day 2 to 3,and the degree of graft steatosis were associated with the average TBil level on the post-operative week 4.But only the AST level on the post-operative day 1 and the average AST level on the post-operative day 2 to 3 were associated with the average TBil level on the 3th and the 6th month post-operation.Conclusion Mild steatotic liver graft can result in increased TBIL level within perioperative period,but the graft function is not affected by it.The average AST level on the post-operative day 2 to 3 can effectively predict the prognosis of the graft.Objective Methods Results Conclusion

The risk factors of splenic arterial steal syndrome after orthotopic liver transplantation / 中华外科杂志

<p><b>OBJECTIVE</b>To discuss the risk factors of splenic arterial steal syndrome (SASS) after orthotopic liver transplantation.</p><p><b>METHODS</b>Twenty-four cases who confirmed SASS after liver transplantation in Tianjin First Central Hospital between June 2005 and June 2013 were analyzed retrospectively. Another 96 cases were selected randomly from those patients of the same time with no complication of SASS patients postoperatively as control group. Clinical data of two groups including diameter of splenic artery and hepatic artery preoperatively, weight of graft, weight of recipients, cold/warm ischemia time, an hepatic period and operation time and so on were collected. Others including hepatic artery peak systolic velocity (PSV), end diastolic velocity (EDV), blood flow resistance index and portal vein average velocity (PVF) on the first day after liver transplantation, the day before diagnosis, the day when diagnosed, the 1, 3, 7 days after treatment in SASS group and on 1, 3, 7, 9, 11, 14 days after liver transplantation in control group. Statistical analysis were made between two groups.</p><p><b>RESULTS</b>The splenic artery/hepatic artery ratio preoperatively and weight of donor liver,and the GRWR in SASS group and control group were 1.26 and 1.00, 1 032 g and 1 075 g, (1.40±0.30)% and (1.82±0.21)% respectively, with significantly statistical differences (Z=-6.40, Z=-2.22, t=-6.50; all P<0.05). The warm ischemia time, the cold ischemia time, the anhepatic period and operation time in SASS group and control group were 3.5 minutes and 4.0 minutes, 10.25 hours and 10.10 hours, 43 minutes and 45 minutes, 8.7 hours and 8.7 hours, with no significantly statistical differences (all P>0.05). RI of hepatic went up gradually in the early time after transplantation while dropped obviously when spleen artery spring coils embolization was received (P<0.01) and trended to stable two weeks later.</p><p><b>CONCLUSIONS</b>Splenic artery/hepatic artery ratio and GRWR are the positive and negative risk factors respectively for SASS. The gradual rising of hepatic RI in the early time after transplantation may be the warning signal SASS and spleen artery spring coils embolization is the effective strategy for SASS after liver transplantation.</p>

Application of hepatitis B surface antigen positive graft in hepatic carcinoma patients receiving liver transplantation / 中华器官移植杂志

Objective To identify the long-term survival of patients with hepatic carcinoma who received hepatitis B surface antigen (HBsAg) positive donor livers.Method A total of 195 patients were enrolled in the study.They were all diagnosed as having hepatic carcinoma with malignant thrombus in portal vein pre-operation and received liver transplantations between 1999 and 2014.The long-term survival between the patients who received HBsAg positive grafts and those who received HBsAg negative grafts was compared.Result There were no differences in ages,preoperative tumor stages and postoperative mortality between the two groups.There was significant difference in survival time between the two groups (Z=-2.038,P =0.042),with the median survival time of 8.83 months (2.50-24.80 months) in HBsAg positive graft group and 13.12 months (6.50-27.65 months) in HBsAg negative graft group,respectively.The long-term survival rate in HBsAg positive graft group was 48％ and that in HBsAg negative graft group was 34.7％ (P =0.740,x2 =0.110).However,the proportion of deaths due to recurrence of tumor was high to 75.8％ in all causes.Conclusion To prolong the survival time,it is safe and feasible to receive HBsAg positive donor livers in patients with hepatic carcinoma in late stage.However,tumor recurrence was still the main causes of deaths in patients post-operation because of the advanced tumor conditions pre-operation.

The clonal origin of diffuse hepatocellular carcinoma / 天津医药

Objective To determine the tumor clonal origin of diffuse hepatocellular carcinoma (D-HCC) and clinical outcome after liver transplantation. Methods Fourteen D-HCC patients who underwent liver transplantation in the Tianjin First Central Hospital between August 2004 to November 2012 were evaluated retrospectively. Their clinical characteristics and data of disease-free survival postoperatively were gathered. Twelve loss of heterozygosity sites (LOH) on high frequency microsatellite were selected. The tumor clonal origin of D-HCC was assessed by the means of PCR-SSCP. Results Of 14 D-HCC patients, intrahepatic metastasis (IM) occurred in 11 cases (11/14), and IM with multicentric occurrence (MO) occurred in 3 cases (3/14). The disease-free survival time was 4.5 to 37.4 months, and the median time was 8.7 months. Conclusion The most frequent tumor clonal origin of D-HCC was IM. Liver transplantation may be the effective treatment for D-HCC.

The cccDNA in HBcAb positive donor may be one of the risk factors in HBV recurrence of hepatitis B-related liver transplantation patients / 中华器官移植杂志

Objective To indentify the relationship between hepatitis B virus covalently closed circular DNA (HBV cccDNA) and postoperative recurrence of HBV in HBcAb positive liver donors by detecting HBV cccDNA in liver from HBcAb positive liver donors.Method Eighty-five of 1200 patients underwent liver transplantation for hepatitis B-related end-stage liver disease in our hospital from January 2007 to January 2010 were retrospectively analyzed.According to the situation of HBV infection in donor liver,the recipients were divided into 3 groups:(1) the experimental group (livers positive for HBcAb,and negative for HBsAg,n =40),(2) control group (livers positive for HBsAg,n =15),and (3) normal group (donor livers without HBV infection,n =30).HBV cccDNA of donors was detected by fluorescence quantitative PCR.Serum HBV and HBV DNA were regularly tested,and biopsy was done in those positive for HBsAg or HBV DNA to confirm HBV recurrence.The relationship between HBV cccDNA and postoperative recurrence of HBV in HBcAb positive liver donors was analyzed.Result The positive rate of cccDNA was 30％ in experimental group (12、40),73.3％ in control group (11/50),and 0 (normal group).The rate of HBV recurrence in experimental,control and normal groups was 10％ (4/40),80％ (12/15) and 3.3％ (1/30) respectively.The rate of HBV recurrence in the experimental group of cccDNA (+) and cccDNA (-) was 7.5％ (3/40),and 2.5％ (1/40).Conclusion The cccDNA in HBcAb positive donors may be one of the risk factors in HBV recurrence of hepatitis B-related liver transplantation patients.The screening of HBV cccDNA in the donor livers positive for HBcAb before liver transplantation is recommended to reduce the positive HBV recurrence and expand the pool of liver donors for patients with HBV-related liver disease.

Risk factors of BK virus infection post renal transplantation / 中华泌尿外科杂志

Objective To analyze the risk factors of BKV infection and compare the real-time PCR procedure and urinary sediment smears of patients checked for decoy cells. Methods The peripheral blood samples of 129 renal recipients were collected. According to the result of PCR, 129 patients were divided into 2 groups:①BKV-DNA(+);②BKV-DNA(-). The sex, age, cold ischemia time, hemotodialysis duration, immunosuppressive agent and other clinical parameters were compared between the 2 groups and a Logistic regression was performed to analyze the risk factors of BKV infection. Results There were 20(15. 5%) patients in BKV-DNA(+), 109(84. 5%)patients in BKV-DNA(-)group. Logistic regression found that the cold ischemia time, hematodialysis duration, living donor were significantly related to the BKV-DNA. The results of the real-time PCR procedure and urinary sediment smears of patients checked for decoy cells were related. Conclusion Real-time fluorescent quantitative PCR and urine decoy cell are good way for detection of BKV infection after renal transplantation. The cold ischemia time and hematodialysis duration and brain death donor were the risk factors of BKV infection post renal transplantation.

Mutation of X region nucleotide sequence of hepatitis B virus DNA in patients with HBV reinfection after Hver transplantation / 中华普通外科杂志

Objective To analyze the mutation of HBV X region nucleotide sequence in patients with HBV reinfection after liver transplantation. Methods In this study 320 patients received liver transplantation due to HBV-related end stage hver diseases between June 2002 and Dec 2003.Postoperatively polymerase chsin reaction was used to aInplify their serum HBV DNA fragments for direct sequence analysis.Patients that were followed-up for 1.5～3 years were enlisted for analysis.Results All the 11 reinfection recipients showed nucleotide mutations in X region mng4ng from 5 to 39 sites after transplantation.An A to T mutation at nt1762 and G to A mutation at nt1764 were found in 6 cases.The mutations at nucleotide fnt)1636～1741 were found in all 11 cases.Condusions The results indicated that mutations of nt 1762 and nt 1764 are very common and immunosuppressants cannot change the mutations in patients with HBV reinfection after liver transplantation.

Pathologic diagnosis of transplantation liver puncture biopsy: clinicopathologic analysis of 906 cases/times / 中华器官移植杂志

Objective To explore the histological morphological features of complications following liver transplantation. Methods In 639 patients with complications following liver transplantation, the percutaneous liver biopsy tissues were stained by HE method. Van Gieson, Masson, PAS, reticulin and immunohistochemical staining were performed. HBsAg, HBcAg, HCVAg, CMV-EA, CMV-LA, CMV pp65, EBVAg and the expression of CK19 were detected. The rejection was graded according to Banff standard and scored with RAI.Results 906 times of liver biopsies in 639 cases were performed. Acute cellular rejection (ACR) was most commonly seen in 386 cases ( 42.61 %), followed by complication of biliary tract (251 cases, 27.70 %), drug-induced liver damage (72 cases, 7.95 %), CMV infection (55 cases, 6.07 %), infection or recurrence of hepatitis virus (B or C) (45 cases, 4.97 %), ischemia-reperfusion injury (42 cases, 4.64 %), chronic rejection (32 cases, 3.53 %), obstruction of efferent tract (6 cases, 0.66 %), recurrence of the primary affection (5 cases, 0.55 %), and non-function of live grafts (4 cases, 0.44 %). The complications in 8 cases were difficult to diagnose ( 0.88 %). Compared with the previous report of complications, the incidence rate of ACR was decreased and that of complication of biliary tract and drug-induced liver damage increased in this study. Conclusion Percutaneous liver biopsy is valuable for the diagnosis of complications. It provides the evidence of settling plan of treatment and improves the survival rate.