A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation.

BACKGROUND & AIMS: Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. METHODS: In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. RESULTS: Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). CONCLUSIONS: HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. IMPACT AND IMPLICATIONS: This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.

Minimizing the risk of small-for-size syndrome after liver surgery.

BACKGROUND: Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant (FLR) may prevent patients from having a curative resection or may result in increased postoperative morbidity and mortality from complications related to small-for-size syndrome (SFSS). DATA SOURCES: This comprehensive review analyzed the principles, mechanism and risk factors associated with SFSS and presented current available options in the evaluation of FLR when planning liver surgery. In addition, it provided a detailed description of specific modalities that can be used before, during or after surgery, in order to optimize the conditions for a safe resection and minimize the risk of SFSS. RESULTS: Several methods which aim to reduce tumor burden, preserve healthy liver parenchyma, induce hypertrophy of FLR or prevent postoperative complications help minimize the risk of SFSS. CONCLUSIONS: With those techniques the indications of radical treatment for patients with liver tumors have significantly expanded. The successful outcome depends on appropriate patient selection, the individualization and modification of interventions and the right timing of surgery.

Liver transplantation for HCC: validation of prognostic power of the RETREAT score for recurrence in a UK cohort.

BACKGROUND: The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC. METHODS: LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria. RESULTS: 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively). CONCLUSION: LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.

Liver Transplantation for Biliary Atresia in Adulthood: Single-Centre Surgical Experience.

BACKGROUND: Biliary atresia (BA) is the most common indicator for liver transplant (LT) in children, however, approximately 22% will reach adulthood with their native liver, and of these, half will require transplantation later in life. The aim of this study was to analyse the surgical challenges and outcomes of patients with BA undergoing LT in adulthood. METHODS: Patients with BA requiring LT at the age of 16 or older in our unit between 1989 and 2020 were included. Pretransplant, perioperative variables and outcomes were analysed. Pretransplant imaging was reviewed to assess liver appearance, spontaneous visceral portosystemic shunting (SPSS), splenomegaly, splenic artery (SA) size, and aneurysms. RESULTS: Thirty-four patients who underwent LT for BA fulfilled the inclusion criteria, at a median age of 24 years. The main indicators for LT were synthetic failure and recurrent cholangitis. In total, 57.6% had significant enlargement of the SA, 21% had multiple SA aneurysm, and SPSS was present in 72.7% of the patients. Graft and patient survival at 1, 5, and 10 years was 97.1%, 91.2%, 91.2% and 100%, 94%, 94%, respectively Conclusions: Good outcomes after LT for BA in young patients can be achieved with careful donor selection and surgery to minimise the risk of complications. Identification of anatomical variants and shunting are helpful in guiding attitude at the time of transplant.

Fatal metabolic stroke in a child with propionic acidemia 11 years post liver transplant.

Propionic acidemia is a rare autosomal recessive inborn error of metabolism caused by a deficiency of propionyl CoA carboxylase which often manifests with frequent metabolic decompensations and risk of neurological injury. Outcomes with medical therapy remain suboptimal. Liver transplantation has been shown to be a therapeutic option for patients and results in a milder phenotype of the disease and partial correction of the enzyme defect. Liver transplantation has been increasingly reported over the last decade and experience in managing these patients is improving. Long-term outcomes are generally good; however, the risk of complications still exists despite transplantation. We report a child who presented with a fatal metabolic stroke 11 years post liver transplant without any biochemical evidence of decompensation. We highlight the need to closely monitor these patients lifelong despite liver transplantation and maintain multidisciplinary working between hepatology and metabolic clinicians.

Sequential Cohort Analysis After Liver Transplantation Shows de Novo Extended Release Tacrolimus Is Safe, Efficacious, and Minimizes Renal Dysfunction.

The use of once-daily extended-release tacrolimus (ERT) is associated with improved long-term graft and patient survival when compared with twice-daily tacrolimus (BDT), but the underlying reasons for differential survival are unclear. The aim of the study was to compare clinical outcomes known to impact on posttransplant survival for de novo BDT and ERT in liver transplantation (LT) recipients. METHODS: We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up. RESULTS: A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3-4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group. CONCLUSIONS: We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.

Liver Transplantation in Children With Propionic Acidemia: Medium-Term Outcomes.

Liver transplantation (LT) for patients with propionic acidemia (PA) is an emerging therapeutic option. We present a retrospective review of patients with PA who underwent LT at a tertiary liver center between 1995 and 2015. A total of 14 children were identified (8 males) with median age at initial presentation of 3 days (range, 0-77 days). Pretransplant median protein restriction was 1 g/kg/day (range, 0.63-1.75 g/kg/day), 71% required supportive feeding, and 86% had developmental delay. Frequent metabolic decompensations (MDs) were the main indication for LT with a median age at transplantation of 2.4 years (range, 0.8-7.1 years). Only 1 graft was from a living donor, and 13 were from deceased donors (4 auxiliary). The 2-year patient survival was 86%, and overall study and graft survival was 79% and 69%, respectively. Three patients died after LT: at 43 days (biliary peritonitis), 225 days (acute-on-chronic rejection with multiorgan failure), and 13.5 years (posttransplant lymphoproliferative disease). Plasma glycine and propionylcarnitine remained elevated but reduced after transplant. Of 11 survivors, 5 had at least 1 episode of acute cellular rejection, 2 sustained a metabolic stroke (with full recovery), and 3 developed mild cardiomyopathy after LT. All have liberalized protein intake, and 9 had no further MDs: median episodes before transplant, 4 (range, 1-30); and median episodes after transplant, 0 (range, 0-5). All survivors made some developmental progress after LT, and none worsened at a median follow-up of 5.8 years (range, 2-23 years). LT in PA significantly reduces the frequency of MDs, can liberalize protein intake and improve quality of life, and should continue to be considered in selected cases.

Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children.

BACKGROUND & AIMS: Liver transplantation (LT) is the most effective treatment for patients with acute liver failure (ALF), but is limited by surgical risks and the need for life-long immunosuppression. Transplantation of microencapsulated human hepatocytes in alginate is an attractive option over whole liver replacement. The safety and efficacy of hepatocyte microbead transplantation have been shown in animal models. We report our experience of this therapy in children with ALF treated on a named-patient basis. METHODS: Clinical grade human hepatocyte microbeads (HMBs) and empty microbeads were tested in immunocompetent healthy rats. Subsequently, 8 children with ALF, who were awaiting a suitable allograft for LT, received intraperitoneal transplantation of HMBs. We monitored complications of the procedure, assessing the host immune response and residual function of the retrieved HMBs, either after spontaneous native liver regeneration or at the time of LT. RESULTS: Intraperitoneal transplantation of HMBs in healthy rats was safe and preserved synthetic and detoxification functions, without the need for immunosuppression. Subsequently, 8 children with ALF received HMBs (4 neonatal haemochromatosis, 2 viral infections and 2 children with unknown cause at time of infusion) at a median age of 14.5 days, range 1 day to 6 years. The procedure was well tolerated without complications. Of the 8 children, 4 avoided LT while 3 were successfully bridged to LT following the intervention. HMBs retrieved after infusions (at the time of LT) were structurally intact, free of host cell adherence and contained viable hepatocytes with preserved functions. CONCLUSION: The results demonstrate the feasibility and safety of an HMB infusion in children with ALF. LAY SUMMARY: Acute liver failure in children is a rare but devastating condition. Liver transplantation is the most effective treatment, but it has several important limitations. Liver cell (hepatocyte) transplantation is an attractive option, as many patients only require short-term liver support while their own liver recovers. Human hepatocytes encapsulated in alginate beads can perform the functions of the liver while alginate coating protects the cells from immune attack. Herein, we demonstrated that transplantation of these beads was safe and feasible in children with acute liver failure.

Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation?

Acute severe presentations of autoimmune hepatitis (AIH) represent a challenge for the transplant community. As a disease, it is poorly characterized, and there is a weak evidence base to guide diagnosis and treatment. Early identification of acute severe AIH is key because it determines the initiation of corticosteroids, which can be lifesaving. However, their use in this setting remains controversial. The Model for End-Stage Liver Disease score, severity of coagulopathy, and grade of encephalopathy may be predictors of outcome with corticosteroid therapy. The optimal timing of liver transplantation (LT) can be difficult to determine and, as such, the decision to proceed to transplantation should not be delayed by protracted courses of corticosteroids. The aim of this review is to better characterize this subset of patients; to differentiate them clinically, serologically, and histologically from chronic AIH and other causes of acute liver failure; and to present the role, predictors, and optimal timings of corticosteroid therapy and LT. Although this review is specific to adults, many principles hold true for the pediatric population.

Liver transplantation for neonatal-onset citrullinemia.

Citrullinemia or ASS deficiency in its classical form presents in the neonatal period with poor feeding, hyperammonemia, encephalopathy, seizures, and if untreated can be fatal. Despite advances in medical therapy, neurocognitive outcomes remain suboptimal. LT has emerged as a potential management option. A retrospective single-center review identified 7 children with a median age of 1.1 years (range, 0.6-5.8) at referral. Five children presented clinically, and 2 were treated prospectively from birth due to positive family history. All patients received standard medical and dietary therapy prior to LT. The indications for LT were frequent metabolic decompensations in 4, elective in 2, and ALF in 1. The median age at LT was 2.4 years (range, 1.3-6.5). Five patients received 6 left lateral segment grafts, one a live unrelated donor left lateral segment as an APOLT graft, and one a cadaveric whole liver graft as APOLT. One child required retransplantation due to hepatic artery thrombosis. Graft and patient survival were 86% and 100%, respectively. Median follow-up is 3.1 years (range, 0.1-4.1), and the median age at follow-up is 5.5 years (range, 4.0-9.8). There have been no metabolic decompensations in 6 children, while 1 patient (with APOLT) developed asymptomatic hyperammonemia with no clinical or histological signs of liver injury, requiring additional medical therapy. Our medium-term experience following LT in citrullinemia is favorable, demonstrating a positive transformation of the clinical phenotype.

Successful pregnancy outcomes following liver transplantation is predicted by renal function.

Liver transplantation (LT) is a successful treatment for both acute liver failure and end-stage liver disease. The number of women of reproductive age undergoing LT is increasing. Pregnancy outcomes are favorable, but there is still a lack of prognostic markers. We aimed to identify factors predictive of adverse pregnancy outcomes in LT recipients. An analysis of all pregnancies occurring in LT recipients from 1989 to 2016 at King's College Hospital was performed. Clinical data of 162 conceptions in 93 women were reviewed. Descriptive and regression analyses were done to examine associations between laboratory markers and hepatological scores with pregnancy outcomes of live birth and preterm birth. Median age at LT was 23 years (range, 1-41 years), with a median age at conception of 30 years (range, 18-47 years). The live birth rate was 75% (n = 121). Of live births, 35% (n = 39/110 available) were delivered preterm. Preconception creatinine levels were higher in patients who had a preterm birth (85 versus 74 µmol/L; P = 0.008), with a preconception estimated glomerular filtration rate (eGFR) <90 mL/minute significantly associated with preterm delivery (P = 0.04). Progressive decline in eGFR predicted outcome, with gestational length declining with increasing chronic kidney disease (CKD) stage: CKD 0-1 = 39 weeks (median), CKD 2 = 37 weeks, and CKD 3 = 35 weeks. The risk of preterm birth was greatest in women with an eGFR <60 mL/minute (P = 0.004). Moreover, hypertension-related complications during pregnancy, such as gestational hypertension, preeclampsia, or eclampsia, were also associated with prematurity (P = 0.01). Women taking steroid-based immunosuppression had an increased risk of infection during pregnancy or postpartum (15% versus 4%; P = 0.02). In conclusion, although the majority of women have a successful pregnancy outcome after LT, preconception renal function predicts pregnancy outcome and steroids increase risk of infection during pregnancy or postpartum. Liver Transplantation 24 606-615 2018 AASLD.

Validation of artificial neural networks as a methodology for donor-recipient matching for liver transplantation.

In 2014, we reported a model for donor-recipient (D-R) matching in liver transplantation (LT) based on artificial neural networks (ANNs) from a Spanish multicenter study (Model for Allocation of Donor and Recipient in España [MADR-E]). The aim is to test the ANN-based methodology in a different European health care system in order to validate it. An ANN model was designed using a cohort of patients from King's College Hospital (KCH; n = 822). The ANN was trained and tested using KCH pairs for both 3- and 12-month survival models. End points were probability of graft survival (correct classification rate [CCR]) and nonsurvival (minimum sensitivity [MS]). The final model is a rule-based system for facilitating the decision about the most appropriate D-R matching. Models designed for KCH had excellent prediction capabilities for both 3 months (CCR-area under the curve [AUC] = 0.94; MS-AUC = 0.94) and 12 months (CCR-AUC = 0.78; MS-AUC = 0.82), almost 15% higher than the best obtained by other known scores such as Model for End-Stage Liver Disease and balance of risk. Moreover, these results improve the previously reported ones in the multicentric MADR-E database. In conclusion, the use of ANN for D-R matching in LT in other health care systems achieved excellent prediction capabilities supporting the validation of these tools. It should be considered as the most advanced, objective, and useful tool to date for the management of waiting lists. Liver Transplantation 24 192-203 2018 AASLD.

Impact of comorbidity on waiting list and post-transplant outcomes in patients undergoing liver retransplantation.

AIM: To determine the impact of Charlson comorbidity index (CCI) on waiting list (WL) and post liver retransplantation (LRT) survival. METHODS: Comparative study of all adult patients assessed for primary liver transplant (PLT) (n = 1090) and patients assessed for LRT (n = 150), 2000-2007 at our centre. Demographic, clinical and laboratory variables were recorded. RESULTS: Median age for all patients was 53 years and 66% were men. Median model for end stage liver disease (MELD) score was 15. Median follow-up was 7-years. For retransplant patients, 84 (56%) had ≥ 1 comorbidity. The most common comorbidity was renal impairment in 66 (44.3%). WL mortality was higher in patients with ≥ 1 comorbidity (76% vs 53%, P = 0.044). CCI (OR = 2.688, 95%CI: 1.222-5.912, P = 0.014) was independently associated with WL mortality. Patients with MELD score ≥ 18 had inferior WL survival (Log-Rank 6.469, P = 0.011). On multivariate analysis, CCI (OR = 2.823, 95%CI: 1.563-5101, P = 0.001), MELD score ≥ 18 (OR 2.506, 95%CI: 1.044-6.018, P = 0.04), and requirement for organ support prior to LRT (P < 0.05) were associated with reduced post-LRT survival. Donor/graft parameters were not associated with survival (P = NS). Post-LRT mortality progressively increased according to the number of transplanted grafts (Log-Rank 18.455, P < 0.001). Post-LRT patient survival at 1-, 3- and 5-years were significantly inferior to those of PLT at 88% vs 73%, P < 0.001, 81% vs 71%, P = 0.018 and 69% vs 55%, P = 0.006, respectively. CONCLUSION: Comorbidity increases WL and post-LRT mortality. Patients with MELD ≥ 18 have increased WL mortality. Patients with comorbidity or MELD ≥ 18 may benefit from earlier LRT. LRT for ≥ 3 grafts may not represent appropriate use of donated grafts.

Breast cancer liver metastases in a UK tertiary centre: Outcomes following referral to tumour board meeting.

INTRODUCTION: To assess the outcomes from multidisciplinary board meetings (MDM) for patients with breast cancer liver metastases (BCLM) and identify prognostic factors for survival. MATERIALS AND METHODS: A retrospective review of MDM records for patients referred with BCLM to a tertiary centre between 2005 and 2016. Patient demographics, clinicopathological factors and intervention type were analysed to find predictive factors for overall survival. RESULTS: 61 patients with BCLM were referred to the MDM. Treatment pathways included surgical resection (n = 23), radiofrequency ablation (RFA, n = 11), or chemotherapy (n = 27). Surgical resection patients had an improved median overall survival compared to chemotherapy (49 v 20mo; p < 0.001). RFA showed comparable survival benefit (37 v 20mo; p = 0.011). Resection and RFA showed no significant difference in survival over one another (49 v 37mo; p = 0.854). Survival analysis identified that resection (p = 0.002) and RFA (p = 0.001) were associated with improved overall survival compared to chemotherapy. Multivariate analysis identified extrahepatic disease (HR = 14.21; p = 0.044) and R0 resection (HR = 0.068; p = 0.023) as prognostic factors. CONCLUSIONS: Surgical resection of BCLM may improve the overall survival in selected patient groups. This study identifies a cohort of patients, without extrahepatic disease and responsive to chemotherapy, who may particularly benefit from surgery.

The 24-hour normothermic machine perfusion of discarded human liver grafts.

Donor organ shortage necessitates use of less than optimal donor allografts for transplantation. The current cold storage preservation technique fails to preserve marginal donor grafts sufficiently. Evidence from large animal experiments suggests superiority of normothermic machine preservation (NMP) of liver allografts. In this study, we analyze discarded human liver grafts that underwent NMP for the extended period of 24 hours. Thirteen human liver grafts which had been discarded for transplantation were entered into this study. Perfusion was performed with an automated device using an oxygenated, sanguineous perfusion solution at normothermia. Automated control was incorporated for temperature-, flow-, and pressure-regulation as well as oxygenation. All livers were perfused for 24 hours; parameters of biochemical and synthetic liver function as well as histological parameters of liver damage were analyzed. Livers were stratified for expected viability according to the donor's medical history, procurement data, and their macroscopic appearance. Normothermic perfusion preservation of human livers for 24 hours was shown to be technically feasible. Human liver grafts, all of which had been discarded for transplantation, showed levels suggesting organ viability with respect to metabolic and synthetic liver function (to varying degrees). There was positive correlation between instantly available perfusion parameters and generally accepted predictors of posttransplant graft survival. In conclusion, NMP is feasible reliably for periods of at least 24 hours, even in highly suboptimal donor organs. Potential benefits include not only viability testing (as suggested in recent clinical implementations), but also removal of the time constraints associated with the utilization of high-risk livers, and recovery of ischemic and other preretrieval injuries (possibly by enabling therapeutic strategies during NMP). Liver Transplantation 23 207-220 2017 AASLD.

Pigmented well-differentiated hepatocellular neoplasm with beta-catenin mutation.

According to the most recent WHO classification of hepatocellular adenomas, a small percentage of inflammatory hepatocellular adenomas presents with mutation in the beta-catenin gene and are at higher risk of malignant transformation. It has been recognized that adenoma-like hepatocellular neoplasms with focal atypia, or in unusual clinical context present with similar cytogenetic and immunohistochemistry characteristics to well-differentiated hepatocellular carcinomas. We report a case of a well-differentiated hepatocellular neoplasm with Dubin-Johnson-like pigment displaying histological features overlapping with a beta-catenin mutated inflammatory adenoma and a well-differentiated hepatocellular carcinoma in a non-cirrhotic liver. The patient was a 48-year-old woman, who was asymptomatic, and had a clinical history of intra-uterine exposure to diethylstilbestrol, previous cancers and past oral contraceptive use. The recently proposed term "well-differentiated hepatocellular neoplasm of uncertain malignant potential" should be applied in such cases to highlight the different pathogenesis and risk of malignancy compared to the typical adenomas, and to suggest a careful and customized clinical management.