Prevention of de novo hepatitis B virus infection in living donor liver transplantation using hepatitis B core antibody positive donors

Exclusion of liver grafts from hepatitis B core antibody (anti-HBc) positive donors to prevent de novo hepatitis B virus (HBV) infection after liver transplantation is not feasible in areas highly endemic for HBV virus like Taiwan, where approximately 80% of adults are anti-HBc(+). The efficacy of lamivudine monotherapy to prevent de novo HBV infection after living donor liver transplantation (LDLT) using grafts from anti-HBc(+) donors remains to be elucidated. From June 1994 to August 2000, LDLT was performed in 42 recipients. Twenty-four of the 42 donors were anti-HBc(+) (57%). Pre-transplant HBV vaccination was given to all recipients irrespective of anti-HBc status at monthly intervals for 3 months. Until December 1997, eight recipients received liver grafts from anti-HBc(+) donors without prophylaxis. Since January 1998, prophylaxis with lamivudine monotherapy was given to 16 recipients receiving liver grafts from anti-HBc(+) donors. De novo HBV infection occurred in three of the eight recipients (37.5%) who did not receive prophylaxis, while none of the 16 recipients given lamivudine developed de novo HBV infection after a mean follow-up of 25 months. Two of the three recipients with de novo HBV infection were anti-HBs(-) and one recipient was anti-HBs(+). Lamivudine was well tolerated, and no side effects were noted. These results suggest that lamivudine monotherapy for recipients receiving anti-HBc(+) liver grafts is a simple, relatively inexpensive and effective prophylactic regimen for prevention of de novo HBV infection. The additive protection provided by vaccine-induced or natural immunity is uncertain.     

The impact of donor cocaine use on the outcome of adult liver transplantation

BACKGROUNDS: To investigate the feasibility of adult liver transplantation from donors with cocaine use. METHODS: Of 807 adult liver transplantations performed between 1994 and 2000, 72 donors (8.9%) were current cocaine users. Donor characteristics and post-transplantation outcomes were retrospectively compared between the 72 cocaine and 126 control group selected from the remaining 735 donors, matched for age and having no history of drug use. RESULTS: Marijuana, opiates and amphetamines were drugs of abuse often present with cocaine. Except for a high incidence of acute alcohol use in the cocaine donors, donor characteristics were comparable. The cocaine group had a significantly higher graft loss within three months of transplant (18.1% vs. 7.9%, p < 0.05), and had a trend toward lower graft survival (76% vs. 86% at one yr). CONCLUSIONS: Potential adverse effect of cocaine and substances concurrently involved on donor liver was suggested. To clarify the distinct acceptance criteria of cocaine users for liver donation, prospective study is warranted.     

Dual hepatitis virus infections in liver transplant: case report and a review of the literature

Abstract: Background: Liver transplantation (LT) using grafts from anti‐HBVcore antibody‐positive (anti‐HBVcAB+) donors carry risk for development of hepatitis B virus (HBV) infection. The long‐term course of hepatitis C virus (HCV) patients receiving anti‐HBVcAB+ grafts is poorly understood. Patients and methods: A patient with chronic hepatitis C received an anti‐HBVc+ graft and developed de novo hepatitis B after four months. We describe the 14 HCV patients who received antiHBVc+ grafts and the condition of disease. Results: Hepatitis B was treated successfully with lamivudine. One year later, breakthrough infection developed with a lamivudine‐resistant mutant. Addition of adefovir led to HBV surface antigen to surface antibody seroconversion after two yr, which was maintained long term. Antiviral therapy was discontinued. Liver biopsy revealed minimal histologic changes up to eight yr post‐LT. Survival of 14 recipients of antiHBVc+ allografts and 180 recipients of antiHBVc‐negative grafts was equal (minimum follow up of five yr). Liver biopsies at four yr showed grade 0/1 and stage 0/1 in >70%; only two patients showed bridging fibrosis. A literature review of dual hepatitis virus infection revealed an overall milder course of hepatitis post‐LT. Conclusion: The outcome of HCV patients receiving anti‐HBc+ grafts is good and may be associated with a milder course of recurrent HCV.     

Outcomes of living donor liver transplantation for hepatitis C virus‐positive recipients in Japan: results of a nationwide survey

A nationwide survey of living donor liver transplantation (LDLT) for hepatitis C virus (HCV)‐positive recipients was performed in Japan. A total of 514 recipients are reported and included in the study. The cumulative patient survival rate at 5 and 10 years was 72% and 63%, respectively. Of the 514 recipients, 142 patients (28%) died until the end of the observation, among which the leading cause was recurrent hepatitis C (42 cases). According to Cox regression multivariate analysis, donor age (>40), non‐right liver graft, acute rejection episode, and absence of a sustained virologic response were independent prognostic factors. Of the 514 recipients, 361 underwent antiviral treatment mainly with pegylated‐interferon and ribavirin (preemptive treatment in 150 patients and treatment for confirmed recurrent hepatitis in 211). The dose reduction rate and discontinuation rate were 40% and 42%, respectively, with a sustained virologic response rate of 43%. In conclusion, patient survival of HCV‐positive recipients after LDLT was good, with a 10‐year survival of 63%. Right liver graft might be preferable for HCV‐positive recipients in an LDLT setting.     

Meta-analysis and meta-regression of outcomes for adult living donor liver transplantation versus deceased donor liver transplantation

Prior single center or registry studies have shown that living donor liver transplantation (LDLT) decreases waitlist mortality and offers superior patient survival over deceased donor liver transplantation (DDLT). The aim of this study was to compare outcomes for adult LDLT and DDLT via systematic review. A meta-analysis was conducted to examine patient survival and graft survival, MELD, waiting time, technical complications, and postoperative infections. Out of 8600 abstracts, 19 international studies comparing adult LDLT and DDLT published between 1/2005 and 12/2017 were included. U.S. outcomes were analyzed using registry data. Overall, 4571 LDLT and 66,826 DDLT patients were examined. LDLT was associated with lower mortality at 1, 3, and 5 years posttransplant (5-year HR 0.87 [95% CI 0.81–0.93], p < .0001), similar graft survival, lower MELD at transplant (p < .04), shorter waiting time (p < .0001), and lower risk of rejection (p = .02), with a higher risk of biliary complications (OR 2.14, p < .0001). No differences were observed in rates of hepatic artery thrombosis. In meta-regression analysis, MELD difference was significantly associated with posttransplant survival (R² 0.56, p = .02). In conclusion, LDLT is associated with improved patient survival, less waiting time, and lower MELD at LT, despite posing a higher risk of biliary complications that did not affect survival posttransplant.     

Clinical analysis of emergency liver transplantation: the role of living donor liver transplantation

The current liver allocation system requires reevaluation because of the advancements in peri‐transplantation care and surgical techniques. And, the role of living donor liver transplantation (LDLT) in an emergency has not been determined yet. Retrospective review of all patients undergoing emergency liver transplantation (LT) from January 2000 to June 2010 was conducted, and clinical data were analyzed. Of the total 505 LTs, 69 patients (13.7%) underwent an emergency LT. Of these, 54 patients (78.3%) underwent LDLT using a right liver, and 15 patients (21.7%) underwent deceased donor liver transplantation (DDLT). The overall hospital mortality was 21.7% (15/69). The leading cause of death after transplantation was sepsis (60.0%). Multivariate analysis demonstrated that a model for end‐stage liver disease (MELD) >33 [hazard ratio (HR), 16.6; 95% confidence interval (CI), 1.443–191.632; p = 0.024] and existence of pre‐transplantation intubation (HR, 18.2; 95% CI, 1.463–225.483; p = 0.024) were independent factors associated with poor survival after emergency LT. LDLT group and DDLT group showed no difference in hospital mortality (p = 0.854) and graft survival (p = 0.861). Thus, MELD score and respiratory insufficiency could be parameters predicting post‐transplant survival. And, LDLT using the right liver could be an appropriate alternative to DDLT in an emergency.     

Prevention of hepatitis B virus recurrence after liver transplantation

Abstract:  Liver transplantation for hepatitis B virus (HBV)-related liver disease has changed from a contraindication to outcomes comparable with non-HBV-related liver transplantations during the last two decades. Mainly the implementation of immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and the use of nucleoside analogs such as lamivudine and adefovir account for this dramatic change. The standard of care in most centers today consists of lamivudine treatment in replicating hepatitis B pre-orthotopic liver transplantation (OLT) and a combination regimen of lamivudine and HBIG post-OLT. With adefovir, a potent antiviral drug became available in recent years that allows for the treatment of patients with lamivudine-resistant tyrosine-methionine-aspartate-aspartate (YMDD)-mutant HBV. In the transplantation setting, first studies indicate that a triple prophylactic therapy consisting of lamivudine, adefovir, and HBIG will become the standard of care for YMDD-mutant-related hepatitis B. With new drugs emerging for the treatment of chronic HBV, there is optimism for new options also in the transplant setting.     

Cost-effective and safe ambulatory long-term immunoprophylaxis with intramuscular instead of intravenous hepatitis B immunoglobulin to prevent reinfection after orthotopic liver transplantation

BACKGROUND: Hepatitis B (HBV)-infected patients receive an anti-HBs immunoprophylaxis [hepatitis B immunoglobulin (HBIG) titre of more than 100 IU/L] in combination with lamivudine to prevent reinfection after orthotopic liver transplantation (OLT). In comparison with intramuscular (i.m.) HBIG, costs for intravenous (i.v.) HBIG are found to be extremely high. We therefore studied patients' outcome (i) after a switch from i.v. to i.m. HBIG and (ii) the outcome after the patients were initially treated with i.m. HBIG after discharge from the hospital. METHODS: (i) Six outpatients were switched from 2000 IU i.v. HBIG (Hepatect) administered every 2 wk to 2000 IU i.m. HBIG (Hepatitis-B-Immunoglobulin Behring) given once a month. (ii) Six other outpatients were directly treated with i.m. HBIG every 4 wk after OLT. All patients also received 100 mg lamivudine/d. RESULTS: Patients switched from i.v. to i.m. HBIG had stable anti-HBs titres (i.v. HBIG: 180 +/- 37 IU/L vs. i.m. HBIG: 173 +/- 23 IU/L). Patients directly treated with i.m. HBIG also had sufficient anti-HBs titres (176 +/- 31 IU/L). Intramuscular application of HBIG was well tolerated by all patients and no side-effects were observed in patients receiving i.m. HBIG. In comparison with the protocol using i.v. HBIG, the costs of i.m. treatment were 60% lower. CONCLUSION: Long-term administration of i.m. HBIG saves up to 60% of the usual costs for i.v. prophylaxis of HBV reinfection in patients after OLT. In combination with lamivudine, long-term i.m. HBIG therapy is as efficient as i.v. HBIG treatment, but its lower costs clearly favour its use in preventing HBV reinfection after OLT.     

Use of middle hepatic vein in right lobe living donor liver transplantation

The harvesting of the middle hepatic vein (MHV) with the right lobe graft for living‐donor liver transplantation allows an optimal venous drainage for the recipient; however, it is an extensive operation for the donor. This is a prospective, nonrandomized study evaluating liver functions and early clinical outcome in donors undergoing right hepatectomy with or without MHV harvesting. From August 2005 to July 2007, a total of 100 donor right hepatectomies were performed with (n = 49) or without (n = 51) the inclusion of the MHV. The decision to take MHV was based on an algorithm that considers various donor and recipient factors. There was no donor mortality in donors in either group. Overall complication rate was higher in MHV (+) donor group, however when remnant liver volume was kept above 30%, complication rates were similar between the groups. The results of this study show that right hepatectomy including the MHV neither affects morbidity nor impairs early liver function in donors when remnant volume is kept above 30%. The decision, therefore, of the extent of right lobe donor hepatectomy should be tailored to the particular conditions considering the graft quality and metabolic demand of the recipient.     

成人活体肝移植

活体肝移植（LDLT）最初作为一种降低等待做肝移植患者死亡率的方法。日本京都大学LDLT开始于1990年6月,移植例数逐年增加,临床应用范围从小儿扩展到成人。肝脏右叶移植物的应用在LDLT具有重要临床意义,已经成为成人间LDLT标准方法。由于肝脏右叶移植物在LDLT移植后成功应用,近年来成人LDLT例数显著增加,自1990年6月至2005年12月,京都大学附属病院已完成了1140例LDLT手术,其中包括477例成人LDLT手术（年龄大于18岁）。HBV和HCV相关性肝硬化和肝癌是LDLT最常见的适应证,截至2005年12月,随访统计结果表明成人LDLT术后总的5年生存率为69．1％。     

Biliary complications after living donor adult liver transplantation.

The highest rate of complications characterizing the adult living donor liver transplantation (ALDLT) are due to biliary problems with a reported negative incidence of 22-64%. We performed 23 ALDLT grafting segments V-VIII without the middle hepatic vein from March 2001 to September 2005. Biliary anatomy was investigated using intraoperative cholangiography alone in the first five cases and magnetic resonance cholangiography in the remaining 18 cases. In 13 cases we found a single right biliary duct (56.5%) and in 10 we found multiple biliary ducts (43.7%). We performed single biliary anastomosis in 17 cases (73.91%) and double anastomosis in the remaining six (26%) cases. With a mean follow up of 644 days (8-1598 days), patient and graft survivals are 86.95% and 78.26%, respectively. The following biliary complications were observed: biliary leak from the cutting surface: three, anastomotic leak: two, late anastomotic strictures: five, early kinking of the choledochus: one. These 11 biliary complications (47.82%) occurred in eight patients (34.78%). Three of these patients developed two consecutive and different biliary complications. Biliary complications affected our series of ALDLT with a high percentage, but none of the grafts transplanted was lost because of biliary problems. Multiple biliary reconstructions are strongly related with a high risk of complication.     

Living donor liver transplantation: effect of the type of liver graft donation on donor mortality and morbidity

To investigate the influence of the type of liver graft donation on donor mortality and morbidity. The clinical course of 87 living liver donors operated on at our center between 2002 and 2009 was retrospectively analysed and data pertaining to all complications were retrieved. No donor mortality was observed and no donor suffered any life‐threatening complication. Four donors (4.6%) developed biliary leakage, nine (10.3%) had to be readmitted to hospital and six (6.9%) required some or other type of reoperation related to the previous liver donation. Reoperations included incisional or diaphragmatic hernia repair (n = 4), biliary leakage repair (n = 1) and segmental colon resection combined with diaphragmatic hernia repair (n = 1). There was a statistically significant difference in hospital stay (P < 0.001), autologous blood transfusions (P < 0.001) and operating time (P < 0.005) when right lobe donations (Segments V–VIII) were compared with left lobe (Segments II–IV) and left lateral lobe (Segments II–III) donations, whereas no difference was found between these groups regarding hospital readmission, operative revisions and the incidence or severity of complications. Right lobe donation was associated with prolonged hospital stay, increased blood transfusions and prolonged operating time when compared with left and left lateral lobe donation, whereas donor mortality and morbidity did not differ between these groups.     

婴幼儿活体肝移植33例

目的 探讨活体肝移植治疗婴幼儿终末期肝病的疗效.方法 回顾性分析2006年10月至2009年9月上海交通大学医学院附属仁济医院33例实施活体肝移植的婴幼儿的临床资料.本组患儿中位年龄10.9个月,平均体质量8.2 kg,供肝均采用肝左外叶.术后采用他克莫司或环孢素A+激素二联方案或在此基础上再加用吗替麦考酚酯的三联方案行免疫抑制治疗.分析评价手术方法、围手术期处理和随访结果.结果 供者和受者手术时间、术中出血量、术中输血量分别为(384±108)min、(183±35)ml、0和(500±103)min、(296±163)ml、(292±159)ml,供肝冷缺血时间为(64±23)min,移植物质量为(249±52)g,移植物质量与受者体质量比为2.1%±0.4%.全部供者均顺利康复,无手术并发症.受者出现肝动脉栓塞3例,门静脉栓塞2例,各类胆道并发症9例,感染11例,急性排斥反应2例,围手术期死亡5例.本组患儿1年累积生存率为85%(28/33).结论 婴幼儿终末期肝病可通过活体肝移植取得理想的效果.外科技术的提高、围手术期管理经验的积累和规范的随访可提高手术成功率和长期生存率.

Abstract：

Objective To evaluate the efficacy of living donor liver transplantation in the treatment of infants with end-stage liver diseases. Methods The clinical data of 33 infants who received living donor liver transplantation at the Renji Hospital of Shanghai Jiaotong University from October 2006 to September 2009 were retrospectively analyzed. The median age of the infants was 10.9 months, and the mean body weight was 8.2 kg.All of the grafts were left lateral lobes. Tacrolimus (or cyclosporine A) + steroid or tacrolimus (or cyclosporine A)+ steroid + mycophenolate mofeti] were applied to the infants to suppress the immune reaction. Operative techniques, perioperative management and results of follow-up were analyzed. Results The mean operation time,blood loss and blood transfusion of the donors were (384±108)minutes, (183±35) ml and O, and the three indexes of the recipients were (500± 103) minutes, (296±163) ml and (292 ± 159) ml , respectively. The cold preservation time of the grafts was (64 ±23)minutes, the mean weight of the grafts was (249 ±52)g, and the mean graft to recipient weight ratio was 2.1% ± 0.4%. All donors recovered smoothly and no complication occurred. Of the recipients, three were complicated with hepatic artery thrombosis, two with portal vein thrombosis,nine with biliary complications, 11 with infection, two with acute rejection and five infants died perioperatively.The one-year cumulative survival rate of the infants was 85% (28/33). Conclusions Infants with end-stage liver diseases could be treated by living donor liver transplantation. The development of surgical techniques and perioperative managements improves the success rate of operation and the long-term survival rate.     

Association of thrombocytopenia with outcome following adult living donor liver transplantation

This study aimed to evaluate the association of postoperative thrombocytopenia with outcome following adult living donor liver transplantation (LDLT) for end‐stage liver disease (ESLD). It was a prospective study of 120 consecutive adult LDLT from September 2012 to May 2015. Preoperative platelet counts (PLTs) and postoperative PLTs were recorded at regular intervals till 3 months after LDLT. Univariate and multivariate analyses were performed. The median pretransplant PLT was 61 × 10⁹/l. The lowest median PLT after LDLT was observed on POD 3. Patients were stratified into low platelet group (n = 83) with PLT <30 × 10⁹/l and high platelet group (n = 37) with PLT ≥30 × 10⁹/l. Patients with PLT <30 × 10⁹/l had statistically significant higher grade III/IV complication (P = 0.001), early graft dysfunction (P = 0.01), sepsis (P = 0.001), and prolonged ascites drainage (P = 0.002). On multivariate analysis, PLT<30 × 10⁹/l was identified as an independent risk factor for grade III/IV complications (P = 0.005). Overall, patients survival was significantly different between two groups (P = 0.04), but this predictive value was lost in patients who survived more than 90 days (P = 0.37). Postoperative PLT of <30 × 10⁹/l was a strong predictor of major postoperative complications and is associated with early graft dysfunction, prolonged ascites drainage, and sepsis. The perioperative mortality rate was high in the thrombocytopenia group.     

Live donor liver transplantation with older donors: Increased long‐term graft loss due to HCV recurrence

Using our prospectively collected database all adult hepatitis C virus (HCV)‐positive patients receiving an adult‐to‐adult LDLT between October 2000 and May 2014 were identified. Outcome of LDLT with grafts from younger (<50 years=128) vs older donors (≥50 years=31) was compared. Post‐transplant graft function, postoperative complications and incidence of HCV recurrence were evaluated. Long‐term graft and patient survival was calculated. No difference in graft function was observed between younger and older grafts. Overall complications were similar between both groups. The severity of complications determined by the Dindo‐Clavien score was similar. Graft loss from HCV recurrence was significantly less frequent in younger grafts (18% vs 62%, P = 0.001). Young vs older livers had a trend toward improved 1‐, 5‐, and 10‐year graft survival (89% vs 87%, 77% vs 69%, 70% vs 55%, P = 0.096), while patient survival was comparable between both groups (91% vs 90%, 78% vs 69%, 71% vs 60%, P = 0.25). In conclusion, LDLT with older vs younger grafts are more frequently associated with long‐term graft loss due to HCV recurrence. Differences in graft survival might be more prominent with prolonged (≥5‐year) follow‐up. Living donor‐recipient matching is particularly important for younger HCV‐positive recipients.     

Re-use of a liver allograft; an exceptional opportunity to enlarge the organ donor pool

Liver allograft re-use is an exceptional way of enlarging the donor pool. We describe here a case of a re-used liver allograft, originating from an insulin-intoxicated donor and transplanted at first into a recipient presenting with hyperacute liver failure due to paracetamol intoxication. Because the original recipient developed an irreversible cerebral oedema, the allograft was re-implanted electively 55.5 h later into a patient with post-viral C cirrhosis and solitary hepatocarcinoma. Both donor and recipient operations were technically successful; liver function after the second use of the graft was normal.     

Living donor liver transplantation in Egypt

In Egypt there is no doubt that chronic liver diseases are a major health concern. Hepatitis C virus (HCV) prevalence among the 15−59 years age group is estimated to be 14.7%. The high prevalence of chronic liver diseases has led to increasing numbers of Egyptian patients suffering from end stage liver disease (ESLD), necessitating liver transplantation (LT). We reviewed the evolution of LT in Egypt and the current status. A single center was chosen as an example to review the survival and mortality rates. To date, deceased donor liver transplantation (DDLT) has not been implemented in any program though Egyptian Parliament approved the law in 2010. Living donor liver transplantation (LDLT) seemed to be the only logical choice to save many patients who are in desperate need for LT. By that time, there was increase in number of centers doing LDLT (13 centers) and increase in number of LDLT cases [2,400] with improvement of the results. Donor mortality rate is 1.66 per 1,000 donors; this comprised four donors in the Egyptian series. The exact recipient survival is not accurately known however, and the one-year, three-year and five-year survival were 73.17%, 70.83% and 64.16% respectively in the International Medical Center (IMC) in a series of 145 adult to adult living donor liver transplantation (AALDLT) cases. There was no donor mortality in this series. LDLT are now routinely and successfully performed in Egypt with reasonable donor and recipient outcomes. Organ shortage remains the biggest hurdle facing the increasing need for LT. Although LDLT had reasonable outcomes, it carries considerable risks to healthy donors. For example, it lacks cadaveric back up, and is not feasible for all patients. The initial success in LDLT should drive efforts to increase the people awareness about deceased organ donation in Egypt.