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Acute liver failure (ALF) and acute-on-chronic liver (ACLF) are distinct phenotypes of liver failure and, thus, need to be compared and contrasted for appropriate management. There has been a significant improvement in the outcomes of these patients undergoing liver transplantation (LT). Survival post-LT for ALF and ACLF ranges between 90% and 95% and 80% and 90% at 1 year, futility criteria have been described in both ALF and ACLF where organ failures define survival. Plasma exchange and continuous renal replacement therapy may serve as bridging therapies. Identifying the futility of LT is as necessary as the utility of LT in patients with ALF and ACLF. The role of regenerative therapies such as granulocyte colony-stimulating factors in ACLF and hepatocyte and xenotransplantation in both conditions remains uncertain. Measures to increase the donor pool through increasing deceased donor transplants in Asian countries, living donations in Western countries, auxiliary liver transplants, and ABO-incompatible liver transplants are necessary to improve the survival of these patients. In this review, we discuss the similarities and differences in clinical characteristics and the timing and outcomes of LT for ALF and ACLF, briefly highlighting the role of bridging therapies and providing an overview of recent advances in the management of ALF and ACLF., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia., (Copyright © 2022. Published by Elsevier Inc.)

There is a paucity of data on the outcome of liver transplantation (LT) in Budd-Chiari Syndrome (BCS) patients who are listed as status 1. The objective of our study was to determine patient or graft survival following LT in status 1 BCS patients. We utilized United Network for Organ Sharing (UNOS) database to identify all adult patients (> 18 years of age) listed as status 1 with a primary diagnosis of BCS in the United States from 1998 to 2018, and analyzed their outcomes and compared it to non-status 1 BCS patients. Four hundred and forty-six patients with BCS underwent LT between 1998 and 2018, and of these 55 (12.3%) were listed as status 1. There was no difference in long-term post-liver transplant or "intention-to-treat" survival from the time of listing to death or the last day of follow-up between status 1 and non-status 1 groups. Graft and patient survival at 5 years for status 1 patients were 75% and 82%, respectively. Cox regression analysis showed that patients listed as status 1 (aHR: 0.45, p < .02) were associated with a better survival. BCS patients listed as status 1 have excellent survival following emergency LT., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background & Aims: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated., Methods: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3-D0)/D0., Results: A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC = 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%., Conclusion: In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort., Lay Summary: The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required., Competing Interests: Conflict of interest EDM: nothing to disclose, AC: nothing to disclose, OC: nothing to disclose, OR: nothing to disclose, JMP: nothing to disclose, PHD: nothing to disclose, FA: nothing to disclose, CS: nothing to disclose, IOH: nothing to disclose, CD: nothing to disclose, AHB: nothing to disclose, SB: nothing to disclose, NG: nothing to disclose, GPP: nothing to disclose, CB: nothing to disclose, MB: nothing to disclose, HF: nothing to disclose, VdL: nothing to disclose, JD: nothing to disclose, FC: nothing to disclose, SR: nothing to disclose, MDG: nothing to disclose, OG: nothing to disclose, FD: nothing to disclose, PP: nothing to disclose, VDM: nothing to disclose, NR: nothing to disclose, PI: nothing to disclose, MS: nothing to disclose, PM: nothing to disclose, HA: nothing to disclose, DS: nothing to disclose, JCDV: nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Laparoscopic sleeve gastrectomy (LSG) is one of the most commonly performed bariatric surgery in recent years, and some modifications have emerged to improve its efficacy. Melissas has described SG plus jejuno-ileal bypass (JIB), which has reported good results in a few studies. We performed this procedure in 21 cases and in one case, we observed acute liver failure (ALF) that has not been reported before., Case Presentation: A 38-year-old female (BMI: 56.1 kg/m 2 ) underwent laparoscopic SG plus JIB. There was no sign of diarrhea, malnutrition or liver failure for eight months and her BMI was 43.0 kg/m 2 . At the 9th month, she was hospitalized for abdominal pain, jaundice and ALF. The patient was treated by plasmapheresis and molecular absorptive recirculation system. She was planned to undergo liver transplantation but died of multiorgan failure on the 40th day of hospitalization., Conclusion: ALF can be observed following SG plus JIB. JIB reversal before compromising liver functions should be taken into consideration., (Copyright © 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Aim: Liver transplantation (LT) has been used as a definitive management for children with end-stage liver disease or acute liver failure. Living-donor LT (LDLT) has been a common type of LT performed in Asian countries, including Japan, where deceased donors are rarely available. However, the neurological complications (NCs) associated with LDLT remain unknown. The purpose of this study was to clarify the characteristics of NCs in children after LDLT., Methods: This study is a retrospective observational study carried out at a tertiary children's hospital in Japan. We studied children who had undergone LDLT between January 2001 and January 2020., Results: We examined 602 cases of LT, of which 559 were LDLT cases (92.9%). NCs after LT were present in 21 cases (3.8%). The most common neurological symptoms were seizure (n = 17), whereas disturbance of consciousness without seizure was observed in four cases. The frequency of NCs for each of the indications was 12.2% for fulminant hepatic failure, 6.5% for metabolic liver disease, and 0.7% for cholestatic liver disease., Interpretation: We report the characteristics of NCs after LDLT in children. The frequency of NCs after LT was high in cases of fulminant hepatic failure and metabolic diseases, who might have had neurological symptoms or impaired consciousness before LT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Transplant centers coordinate complex care in acute liver failure (ALF), for which liver transplant (LT) can be lifesaving. We studied associations between waitlist outcomes and center (1) ALF waitlist volume (low: <20; medium: 20-39; high: 40+ listings) and (2) total LT volume (<600, 600-1199, 1200+ LTs) in a retrospective cohort of 3248 adults with ALF listed for LT at 92 centers nationally from 2002 to 2019. Predicted outcome probabilities (LT, died/too sick, spontaneous survival [SS]) were obtained with multinomial regression, and observed-to-expected ratios were calculated. Median center outcome rates were 72.6% LT, 18.2% died/too sick, and 6.1% SS. SS was significantly higher with greater center ALF volume (median 0% for low-, 5.9% for medium-, and 8.6% for high-volume centers; P = .039), while waitlist mortality was highest at low-volume centers (median 21.4%, IQR: 16.1%-26.7%; P = .042). Significant heterogeneity in center performance was observed for waitlist mortality (observed-to-expected ratio range: 0-4.1) and particularly for SS (0-6.4), which persisted despite accounting for recipient case mix. This novel study demonstrates that increased center experience is associated with greater SS and reduced waitlist mortality for ALF. More-focused management pathways are needed to improve ALF outcomes at less-experienced centers and to identify opportunities for improvement at large., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Limited data exist regarding the impact of donation after circulatory death (DCD) allografts on outcomes following liver transplantation in fulminant hepatic failure (FHF). Utilizing the Scientific Registry of Transplant Recipients (SRTR), we compared outcomes after DCD in FHF to donation after brain death (DBD) in FHF and DCD in non-FHF over a 15-year period. Primary outcome measures were graft and patient survival. A total of 117, 3437, and 4379 recipients underwent DCD-FHF, DBD-FHF and DCD-non-FHF, respectively. One-year graft survival in DCD-FHF was inferior to DBD-FHF (72.9% vs. 83.8%, p = .002), but comparable to DCD-non-FHF (72.9% vs. 82.7%, p = .23). However, 3- and 5-year graft survival in DCD-FHF were comparable to DBD-FHF (67.9 vs. 77.6%, p = .63; 57.8% vs. 73.2%, p = .27) and DCD-non-FHF (67.9% vs. 72.9%, p = .44; 57.8% vs. 66.6%, p = .06). One-, 3-, and 5-year patient survival were also comparable among the three groups. Graft and patient survival in DCD-FHF improved over the study period. Multivariable analysis identified recipient age, male gender, African American ethnicity, donor age, and cold ischemia time as predictors of graft and patient survival in FHF, while DCD status was only predictive of graft survival. Long-term graft survival and patient survival in DCD-FHF are comparable to DBD-FHF and DCD-non-FHF. Consideration of DCD in FHF could help expand the donor pool in this subset of critically ill patients., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Liver transplantation is considered the ultimate solution for patients with end-stage chronic liver disease or acute liver failure. Patients with liver transplant need special care starting from preoperative preparation, surgical intervention ending with postoperative care. Transplanted patients have to receive immunosuppressive therapy to prevent rejection. Such a state of immune suppression could predispose to different types of infections in liver transplant recipients. Currently, the world is suffering a pandemic caused by a new strain of the coronavirus family called COVID-19. Certain infection control precautions are needed to protect immunocompromised and vulnerable patients, including liver transplant candidates and recipients from acquiring COVID-19 infection. Restricting non-transplant elective surgical procedures, managing transplant patients in separate outpatient clinics, and in-patient wards can prevent transmission of infection both to patients and healthcare workers. Telemedicine can help in the triage of patients to screen for symptoms of COVID-19 before their regular appointment. Management of immunosuppressive therapy and drug-drug interactions in liver transplant recipients infected with COVID-19 should be cautiously practiced to prevent rejection and effectively treat the underlying infection. In this report, we are trying to summarize available evidence about different aspects of the management of liver transplant candidates and recipients in the era of COVID-19., (Copyright © 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019. Published by Elsevier B.V.)

Acute liver failure (ALF) is defined as severe hepatic dysfunction (marked transaminases elevation, detoxification disorder (jaundice and coagulopathy with international normal ratio (INR) > 1.5), the presence of hepatic encephalopathy, and exclusion of underlying chronic liver disease, and a secondary cause like sepsis or cardiogenic shock. Reasons for ALF include paracetamol and warfarin toxicity, autoimmune and viral (mainly hepatitis B and E) hepatitis, and herbal and dietary supplements. Even in terms of meticulous and careful review of the patient, around 20-30% of the reasons remains unknown. In order of its rarity, a randomized controlled trial could hardly be done. However, because of improved ICU treatment, the mortality, even in the advanced stage of ALF decreased. However, in 5-10% of the cases an emergency transplantation is required. This justifies the treatment of this patient cohort in institutions that can provide this kind of treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background & Aims: Severe acute liver injury is a grave complication of exertional heatstroke. Liver transplantation (LT) may be a therapeutic option, but the criteria for LT and the optimal timing of LT have not been clearly established. The aim of this study was to define the profile of patients who require transplantation in this context., Methods: This was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related severe acute liver injury with a prothrombin time (PT) of less than 50%. A total of 24 male patients were studied., Results: Fifteen of the 24 patients (median nadir PT: 35% [29.5-40.5]) improved under medical therapy alone and survived. Nine of the 24 were listed for emergency LT. At the time of registration, the median PT was 10% (5-12) and all had numerous dysfunctional organs. Five patients (nadir PT: 12% [9-12]) were withdrawn from the list because of an elevation of PT values that mainly occurred between day 2 and day 3. Ultimately, 4 patients underwent transplantation as their PT persisted at <10%, 3 days (2.75-3.25) after the onset of exertional heatstroke, and they had more than 3 organ dysfunctions. Of these 4 patients, 3 were still alive 1 year later. Histological analysis of the 4 explanted livers demonstrated massive or sub-massive necrosis, and little potential for effective mitoses, characterised by a "mitonecrotic" appearance., Conclusion: The first-line treatment for exertional heatstroke-related severe acute liver injury is medical therapy. LT is only a rare alternative and such a decision should not be taken too hastily. A persistence of PT <10%, without any signs of elevation after a median period of 3  days following the onset of heatstroke, was the trigger that prompted LT, was the trigger adopted in order to decide upon LT., Lay Summary: Acute liver injury due to heatstroke can progress to acute liver failure with organ dysfunction despite medical treatment; in such situations, liver transplantation (LT) may offer a therapeutic option. The classic criteria for LT appear to be poorly adapted to heatstroke-related acute liver failure. We confirmed thatmedication is the first-line therapy acute liver injury caused by heatstroke, with LT only rarely necessary. A decision to perform LT should not be made hastily. Fluctuations in prothrombin time and the patient's clinical status should be considered even in the event of severe liver failure., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Patients receiving treatment for tuberculosis are at risk of developing acute liver failure due to the hepatotoxicity of antitubercular drugs. We aimed to describe our experience with liver transplantation from deceased donors in this situation., Methods: We identified patients undergoing transplantation for acute liver failure due to antitubercular drugs in our prospectively maintained database., Results: Of 81 patients undergoing transplantation for acute liver failure, 8 cases were attributed to antitubercular drugs during the period of 2006-2016. Regarding the time of tuberculosis treatment until the onset of jaundice, patients were on antitubercular drugs for a mean of 64.7 days (21-155 days). The model for end-stage liver disease (MELD) score of patients ranged from 32 to 47 (median 38), and seven patients underwent transplantation under vasopressors. The 1-year survival was 50%. Three patients died during the week following transplantation due to septic shock (including a patient with acute liver failure due to hepatic/disseminated tuberculosis), and the remaining patient died 2 months after transplantation due to pulmonary infection. There were 2 cases of mild rejection and 1 case of moderate rejection. Of the surviving patients, all were considered cured of tuberculosis after alternative drugs were given., Conclusion: Patients arrived very sick and displayed poor survival after deceased donor transplantation.

Background: The reported mortality rate of mushroom-induced acute liver failure with conventional treatment is 1.4%-16.9%. Emergency liver transplantation may be indicated and can be the only curative treatment option. This study aimed to assess the prognostic value of criteria for emergency liver transplantation in predicting 28-day mortality in patients with mushroom-induced acute liver injury., Methods: A retrospective cohort study was performed between January 2005 and December 2015. All adult patients aged≥18 years admitted with mushroom intoxication at our emergency department were evaluated. All patients with acute liver injury, defined as elevation of serum liver enzymes (>5 times the upper limit of normal, ULN) or moderate coagulopathy (INR > 2.0) were included. The ability of the King's College, Ganzert's, and Escudié's criteria to predict 28-day mortality was evaluated., Results: Of the 23 patients with acute liver injury following mushroom intoxication, 10 (43.5%) developed acute liver failure and subsequently died. The mean time interval from ingestion to death was 11.3 ± 6.6 days. Eight patients fulfilled Ganzert's criteria, while 10 patients fulfilled the King's College and Escudié's criteria for emergency liver transplantation. King's College and Escudié's criteria had 100% accuracy in predicting 28-day mortality; however, Escudié's criteria were able to identify fatal cases earlier., Conclusions: Escudié's criteria demonstrated the best performance with 100% accuracy and the ability to promptly identify fatal cases of mushroom-induced acute liver failure., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Liver transplantation has emerged as a highly efficient treatment for a variety of acute and chronic liver diseases. However, organ shortage is becoming an increasing problem globally, limiting the applicability of liver transplantation. In addition, potential recipients are becoming sicker, thereby increasing the risk of losing the graft during transplantation or in the initial postoperative period after liver transplantation (three months). This trend is challenging the model for end-stage liver disease allocation system, where the sickest candidates are prioritised and no delisting criteria are given. The weighting of the deontological demand for "equity", trying to save every patient, regardless of the overall utility; and "efficiency", rooted in utilitarianism, trying to save as many patients as possible and increase the overall quality of life of patients facing the same problem, has to be reconsidered. In this article we are aiming to overcome the widespread concept of futility in liver transplantation, providing a definition of potentially inappropriate liver transplantation and giving guidance on situations where it is best not to proceed with liver transplantation, to decrease the mortality rate in the first three months after transplantation. We propose "absolute" and "relative" conditions, where early post-transplant mortality is highly probable, which are not usually captured in risk scores predicting post-transplant survival. Withholding liver transplantation for listed patients in cases where liver transplant is not deemed clearly futile, but is potentially inappropriate, is a far-reaching decision. Until now, this decision had to be discussed extensively on an individual basis, applying explicit communication and conflict resolution processes, since the model for end-stage liver disease score and most international allocation systems do not include explicit delisting criteria to support a fair delisting process. More work is needed to better identify cases where transplantation is potentially inappropriate and to integrate and discuss these delisting criteria in allocation systems, following a societal debate on what we owe to all liver transplant candidates., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Acute liver failure (ALF) is a multisystem disease with severe impairment of liver function of acute onset. The Paediatric End-stage Liver Disease (PELD) score is used as a predictor of mortality in chronic liver disease, however experience is limited in ALF., Objectives: To evaluate the aetiology and outcomes of children with ALF in a Children's Liver Transplant Centre, and to investigate the validity of PELD as a prognostic indicator., Patients and Methods: A retrospective study was conducted on patients diagnosed with ALF in our hospital from 2000 to 2013 using the criteria of the Paediatric ALF Study Group., Results: The study included 49 patients with an age range 0-14years. The most frequent aetiologies were: indeterminate (36.7%) and metabolic (26.5%). Liver transplant (LT) was required by 42.8%, and there were 16.3% deaths. Patients with higher levels of bilirubin, INR, or encephalopathy were more likely to require a liver transplant, yielding an OR for INR 1.93. A cut-off of 27 in the PELD score according to the ROC curve showed a sensitivity of 86% and a specificity of 85%, predicting a worse outcome (AUC: 0.90; P<.001). The survival of patients with ALF without transplantation seems more likely in those who have low values of PELD and absence of encephalopathy, with a RR of 0.326., Conclusions: ALF patients with a high PELD score and the presence of encephalopathy had worse outcomes. The PELD score could be a useful tool to establish the optimum time for inclusion in the transplant list, however further studies are still needed., (Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population., Methods: The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate., Results: The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and >15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p<0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (>10,000) had a significant poorer long-term graft survival (p=0.03)., Conclusion: In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Liver transplantation (LT) is a life-saving and curative treatment for Wilson disease (WD), providing restoration of function of the liver and mitigation of portal hypertension. Indications for LT in patients with WD include acute liver failure or end-stage liver disease not treatable by medical therapy. LT is also used to treat hepatocellular carcinoma when it develops in patients with WD when tumor resection is not feasible. LT solely for neurologic or psychiatric WD remains controversial. Living liver donation as well as cadaveric orthotopic and auxiliary LT are options for transplantation for WD. Outcomes for LT for WD are excellent, and supportive measures while awaiting transplantation help bridge the patient to a more successful outcome. Future hepatocyte or stem cell transplantation may augment or supplant current LT for WD., (© 2017 Elsevier B.V. All rights reserved.)

We report the outcome of live donor liver transplantation (LDLT) for patients suffering from acute liver failure (ALF). From 2006 to 2013, all patients with ALF who received a LDLT (n = 7) at our institution were compared to all ALF patients receiving a deceased donor liver transplantation (DDLT = 26). Groups were comparable regarding pretransplant ICU stay (DDLT: 1 [0-7] vs. LDLT: 1 days [0-10]; p = 0.38), mechanical ventilation support (DDLT: 69% vs. LDLT: 57%; p = 0.66), inotropic drug requirement (DDLT: 27% vs. LDLT: 43%; p = 0.64) and dialysis (DDLT: 2 vs. LDLT: 0 patients; p = 1). Median evaluation time for live donors was 24 h (18-72 h). LDLT versus DDLT had similar incidence of overall postoperative complications (31% vs. 43%; p = 0.66). No difference was detected between LDLT and DDLT patients regarding 1- (DDLT: 92% vs. LDLT: 86%), 3- (DDLT: 92% vs. LDLT: 86%), and 5- (DDLT: 92% vs. LDLT: 86%) year graft and patient survival (p = 0.63). No severe donor complication (Dindo-Clavien ≥3 b) occurred after live liver donation. ALF is a severe disease with high mortality on liver transplant waiting lists worldwide. Therefore, LDLT is an attractive option since live donor work-up can be expedited and liver transplantation can be performed within 24 h with excellent short- and long-term outcomes., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Aplastic anemia (AA) has been observed in nearly a third of patients undergoing liver transplantation (LT) for non-A-E fulminant hepatic failure (FHF). Few of these patients have been successfully managed with sequential LT and bone marrow transplantation (BMT). No causative agent has been identified for the FHF or AA in these reported cases. At our center, two patients, aged 15 years and 7 years, respectively, underwent sequential living-related LT and living-unrelated BMT. These patients are 10/9 years and 5/4 years post-LT/BMT. Human parvovirus B19 (HPV-B19) was established as the causative agent for FHF in both these patients by polymerase chain reaction. This report presents the first two cases associating HPV-B19 with FHF and AA who underwent sequential LT and BMT with excellent outcomes., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The established procedure for ABO-incompatible liver transplantation (ABO-I LT) was too complicated to be used in case of emergency. We developed a protocol consisting of rituximab and intravenous immunoglobulin (IVIG) for ABO-I LT in patients with acute liver failure (ALF)., Methods: The data from 101 patients who had undergone liver transplantation (LT) for ALF were retrospectively analyzed. The patients were divided into two groups: ABO-compatible liver transplantation group (ABO-C LT, n=66) and ABO-I LT group (n=35). All the patients in the ABO-I LT group received a single dose of rituximab (375 mg/m2) and IVIG (0.4 g/kg per day) at the beginning of the operation. IVIG was administered for 10 consecutive days after LT. Plasma exchange, splenectomy and graft local infusion were omitted in the protocol. Quadruple immunosuppressive therapy including basiliximab, corticosteroids, tacrolimus and mycophenolatemofetil was used to reinforce immunosuppression., Results: The 3-year cumulative patient survival rates in the ABO-I LT and ABO-C LT groups were 83.1% and 86.3%, respectively (P>0.05), and the graft survival rates were 80.0% and 86.3%, respectively (P>0.05). Two patients (5.7%) suffered from antibody-mediated rejection in the ABO-I LT group. Other complications such as acute cellular rejection, biliary complication and infection displayed no significant differences between the two groups., Conclusions: The simplified treatment consisting of rituximab and IVIG prevented antibody-mediated rejection for LT of blood-type incompatible patients. With this treatment, the patients did not need plasma exchange, splenectomy and graft local infusion. This treatment was safe and efficient for LT of the patients with ALF.

The case for using emergency liver transplantation in acute liver failure was made two decades ago by a series of single centre experiences. The development of models identifying a poor prognosis assisted the selection of patients for liver transplantation but none of these delivers both high sensitivity and specificity for prediction of death. Enhanced sensitivity favours the individual patient while enhanced specificity targets the pool of organs available at those who will derive greatest benefit. The non-transplant survival rates have improved considerably for certain cohorts of patients and these prognostic models have not been adjusted to reflect these changes. The presumption of transplant benefit can no longer be taken as established in paracetamol-related acute liver failure and a policy review is appropriate. In other scenarios, such as seronegative hepatitis and the phenotype of sub-acute liver failure, spontaneous survival rates remain low and the basis for liver transplantation remains sound. Outcomes after liver transplantation are improving but are not yet comparable to elective transplantation. The understanding of factors associated with failure after liver transplantation is improving but accurate definition of futility has not yet been attained., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: An acetominophen overdose (AOD) is the leading cause of acute liver failure (ALF) in the UK and USA. For patients who meet the King's College Hospital criteria, (mortality risk > 85%), an emergency orthotopic liver transplantation (OLT) is conventionally performed with subsequent life-long immunosuppression. A new technique was developed in 1998 for AOD-induced ALF where a subtotal hepatectomy (right hepatic trisectionectomy) and whole graft auxiliary liver transplant (WGALT) was performed with complete withdrawal of immunosupression during the first year post-operatively., Results: During 1998-2010, 68 patients were listed for an emergency transplantation for AOD ALF at our institution: 28 died waiting, 16 underwent OLT and 24 a subtotal hepatectomy with WGALT. Eight OLT (50%) and 16 WGALT remain alive (67%); actuarial survival at 5 years OLT 50%, WGALT 63%, P = 0.37. All patients who had successful WGALT are off immunosuppression. Poor prognostic factors in the WGALT group included higher donor age (40.4 versus 53.9, P = 0.043), requirements for a blood transfusion (4.3 versus 7.6, P = 0.0043) and recipient weight (63.1 versus 54 kg, P = 0.036)., Conclusion: Although OLT remains standard practice for AOD-induced ALF, life-long immunosuppression is required. A favourable survival rate using a subtotal hepatectomy and WGALT has been demonstrated, and importantly, all successful patients have undergone complete immunosuppression withdrawal. This technique is advocated for patients who have acetominophen hepatotoxicity requiring liver transplantation., (© 2013 International Hepato-Pancreato-Biliary Association.)

Background: The timing and selection of patients for liver transplantation in acute liver failure are great challenges. This study aimed to investigate the effect of Glasgow coma scale (GCS) and APACHE-II scores on liver transplantation outcomes in patients with acute liver failure., Method: A total of 25 patients with acute liver failure were retrospectively analyzed according to age, etiology, time to transplantation, coma scores, complications and mortality., Results: Eighteen patients received transplants from live donors and 7 had cadaveric whole liver transplants. The mean duration of follow-up after liver transplantation was 39.86+/-40.23 months. Seven patients died within the perioperative period and the 1-, 3-, 5-year survival rates of the patients were 72%, 72% and 60%, respectively. The parameters evaluated for the perioperative deaths versus alive were as follows: the mean age of the patients was 33.71 vs 28 years, MELD score was 40 vs 32.66, GCS was 5.57 vs 10.16, APACHE-II score was 23 vs 18.11, serum sodium level was 138.57 vs 138.44 mmol/L, mean waiting time before the operation was 12 vs 5.16 days. Low GCS, high APACHE-II score and longer waiting time before the operation (P<0.01) were found as statistically significant factors for perioperative mortality., Conclusion: Lower GCS and higher APACHE-II scores are related to poor outcomes in patients with acute liver failure after liver transplantation.

Background & Aims: Acute liver failure (ALF) is a rapidly progressive critical illness with high mortality. Complex intensive care unit (ICU) protocols and emergency liver transplantation (ELT) are now often available, but rarity and severity of illness have limited its study and evidence-base for care. We reviewed patients treated over a 35-year period at a specialist high-volume ICU, quantifying changes in disease aetiology, severity and evolution of ICU support and ELT use and outcome., Methods: Review of adult patients admitted during the period 1973-2008, with acute liver dysfunction and coagulopathy with overt hepatic encephalopathy (ALF) and those without (acute liver injury; ALI)., Results: 3305 patients fulfilled inclusion criteria, 2095 with ALF. Overall hospital survival increased from 30% in 1973-78 to 76% in 2004-08; in ALF from 17% to 62% (both p<0.0001). In ALF patients treated without ELT, survival rose from 17% to 48% (p<0.0001); in those undergoing ELT (n=387) from 56% in 1984-88 to 86% in 2004-08 (p<0.01). Coincident with drug sales-restriction, paracetamol-related admissions fell significantly. Viral admissions fell from 56% to 17% of non-paracetamol cases (p<0.0001). Admission markers of liver injury severity fell significantly and the proportion of patients with intracranial hypertension (ICH) fell from 76% in 1984-88 to 20% in 2004-08 (p<0.0001). In those with ICH, mortality fell from 95% to 55% (p<0.0001)., Conclusions: The nature and outcome of ALF have transformed over 35 years, with major improvements in survival and a fall in prevalence of cerebral oedema and ICH, likely consequent upon earlier illness recognition, improved ICU care, and use of ELT., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4-6 weeks after liver transplantation are set too high (10-15 ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes., Methods: Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995-2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1 ± 2.5. Median follow-up was 7.3 years (IQR 3.9-10.5). Early tacrolimus exposure (<15 days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression., Results: Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7 ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7 ng/ml (41.2%) (p = 0.004). Mean tacrolimus TC 7-10 ng/ml within 15 days after LT were associated with reduced risk of graft loss (RR = 0.46; p = 0.014) compared to TC 10-15 ng/ml. A peak TC>20 ng/ml within this period was independently related to higher mortality (RR = 1.67; p = 0.005), particularly due to cardiovascular events, infections and malignancy (RR = 2.15; p = 0.001). Early tacrolimus exposure did not influence chronic rejection (p = 0.58), or chronic renal impairment (p = 0.25)., Conclusions: During the first 2 weeks after LT, tacrolimus TC between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Liver transplantation for acute liver failure (ALF) still has a high early mortality. We evaluated changes during 20 years, and identified risk factors for poor outcome., Methods: Donor, graft, and recipient variables from the European Liver Transplant Registry database (January 1988-June 2009), were analysed. Aetiologies and time periods were compared. Three and 12-month survival models were generated from separate training data sets, which were validated. A sub-analysis was performed for recipient older than 50 years., Results: Four thousand nine hundred and three patients were evaluated. One, 5- and 10-year patient, and graft survival rates were 74%, 68%, 63%, and 63%, 57%, 50%, respectively. Survival was better in 2004-2009 compared to previous quinquennia (p<0.001), despite donors >60 years increased from 1.8% to 21%. A higher incidence of suicide or non-adherence occurred in paracetamol-related ALF (p<0.001). Death or graft loss were independently associated with male recipients (adjusted OR 1.25), recipient >50 years (1.26), incompatible ABO matching (1.93), donors >60 years (1.21), and reduced size graft (1.54). For both 3- and 12-month models, incompatible ABO matching, non-viral aetiology, reduced size graft, and non-UW preservation fluid were associated with increased mortality/graft loss, whereas male recipients and age >50 years were associated only at 12 months. Both models had reasonable discriminative ability with good calibration at 3 months. Recipients >50 years, combined with donors >60 years resulted in 57% mortality/graft loss within the first year., Conclusions: Survival after liver transplantation has improved despite increases in donor/recipient age. Recipients >50 years paired with donors >60 years had a very high mortality/graft loss within the first year., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to analyze the hepatic differentiation potential of human umbilical cord blood-derived mesenchymal stem cells (hUCBMSCs) after transplantation into severe combined immune deficiency (SCID) mice with liver injury induced by D-galactosamine/lipopolysaccharide (GalN/LPS) and to explore the possibility that cells can partially repair GalN/LPS-induced hepatic damage., Methods: Mononuclear cells (MNCs) were isolated from fresh human umbilical cord blood, characterized by flow cytometry, and then transplanted into GalN/LPS-injured mice. Specimens were collected at 7, 14, 21, and 28 days after hUCBMSC transplantation. Histopathological changes were analyzed by hematoxylin and eosin staining. Polymerase chain reaction (PCR) for a specific marker of human cells, the human Alu sequence, was performed to locate exogenous hUCBMSCs in mouse livers. Expression of human hepatocyte-specific markers such as human albumin (hALB), human alpha-fetoprotein (hAFP), human cytokeratin 18 (hCK18), and human cytokeratin 19 (hCK19) were analyzed by reverse transcriptase (RT)-PCR and immunohistochemical staining., Results: The hUCBMSCs were positive for the human MSC-specific markers CD271, CD29, CD90, CD105, and CD73, but negative for CD31, CD79b, CD133, CD34, and CD45. Histological findings showed that the hepatic damage in mice was attenuated after hMSC administration, and liver architecture was much better preserved. Human cells in the injured liver of recipient mice were detected by PCR for the human Alu sequence. In addition, expression of markers of hepatic lineage, including hALB, hAFP, hCK18, and hCK19, was detected by immunohistochemistry and RT-PCR in mouse livers after hUCBMSC transplantation, suggesting the formation of hepatocyte-like cells in vivo., Conclusion: MSCs from hUCB exhibit the potential to differentiate into hepatocyte-like cells in the livers of hUCB-transplanted mice as well as partially repair the liver damage induced by GalN/LPS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: To study and evaluate the immunosafety of our newly developed multilayer flat-plate bioartificial liver (BAL) in treatment of canines with acute liver failure., Methods: Fresh porcine hepatocytes and bone marrow mesenchymal stem cells were cocultured in new BAL. Ten canine models with acute liver failure were set up through D-galactosamine administration; 24 hours after administration, the beagles were randomly allocated to a 6-hour treatment with the BAL. The beagles were divided into 2 groups by treatment times. Group 1 beagles (n = 5) received a single BAL treatment. Group 2 beagles (n = 5) received 3 BAL treatments. The hemodynamic, hematologic response and humoral immune responses to BAL therapy were studied before and after treatments., Results: All beagles remained hemodynamically and hematologically stable during BAL treatments. The levels of IgG and IgM were similar before and after treatment after a single treatment. In addition, the level of CH50 in group 1 slightly decreased after the initiation of BAL treatment, and then the level recovered to baseline quickly after treatments. Time-course changes of the levels of antibodies and CH50 after 3 treatments in group 2 were similar to group 1. Only trace levels of IgG were detected in BAL medium after treatments., Conclusion: The multilayer flat-plate BAL showed a great immunosafety in the treatment of canines with acute liver failure and exhibited a good prospect of its use in clinic.

Liver transplantation is now an integral part of the management of acute liver failure. The challenge for clinicians is to select the appropriate candidates with a combination of need and high likelihood of benefiting from the transplant. This is achieved through a combination of prognostic modelling and ongoing clinical evaluation. Although the outcomes after liver transplantation are good the survival rates do not quite match those achieved after elective transplantation., (Copyright © 2012. Published by Elsevier Ltd.)

Orthotopic liver transplantation (OLT) represents the only reliable therapeutic approach for acute liver failure (ALF), liver failure associated to end-stage chronic liver diseases (CLD) and non-metastatic liver cancer. The clinical impact of liver failure is relevant because of the still high ALF mortality and the increasing worldwide prevalence of cirrhosis that, in turn, is the main predisposing cause for hepatocellular carcinoma (HCC). Moreover, in the next decade because an increased number of patients reaching end-stage disease and requiring OLT may face a shortage of donor livers. This clinical scenario led several laboratories to explore the feasibility and efficiency of alternative approaches, involving cellular therapy, to counteract liver failure. The present chapter overviews results and concepts emerged from recent experimental and clinical studies in which adult or embryonic hepatocytes, hepatic stem/progenitor cells, induced pluripotent stem (iPS) cells as well as extrahepatic stem cells have been used as putative transplantable cell sources., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Stem cell-based therapies are emerging as important and promising methods in the treatment of end-stage liver disease. This study is aimed to evaluate the effects of human umbilical cord blood mesenchymal stem cell (HUCBMSC) transplantation in acute hepatic necrosis (AHN)., Methods: Green fluorescent protein (GFP)-labeled HUCBMSCs were injected into the liver of rats in which AHN was induced by carbon tetrachloride, and the migration of these cells in liver slices was evaluated from 48 hours to 4 weeks post-transplantation. The transdifferentiation status of the HUCBMSCs was evaluated using immunohistochemistry and real-time reverse transcription-polymerase chain reaction, and survival rates were statistically analyzed., Results: Dispersed GFP fluorescence was observed along the portal area 48 hours after transplantation. One week post-transplantation, GFP-positive cells were found in necrotic liver areas, and GFP-positive cells persisted after 4 weeks. Immunohistochemistry and real-time polymerase chain reaction analysis showed that transplanted HUCBMSCs expressed several human liver tissue-specific markers in rats with AHN. Statistical analysis revealed that rats with AHN that were transplanted with HUCBMSCs had significantly lower death rates after 48 hours than those receiving no HUCBMSCs., Conclusion: HUCBMSC transplantation can significantly improve the survival of rats with AHN. The underlying mechanisms involved may include the transdifferentiation of HUCBMSCs into hepatocyte-like cells and targeted migration of these cells to liver lesion sites.

Background: Acute hepatic failure (AHF) is a devastating clinical syndrome with a high mortality rate. The outcome of AHF varies with etiology, but liver transplantation (LT) can significantly improve the prognosis and survival rate of such patients. This study aimed to detect the role of LT and artificial liver support systems (ALSS) for AHF patients and to analyze the etiology and outcome of patients with this disease., Methods: A retrospective analysis was made of 48 consecutive patients with AHF who fulfilled the Kings College Criteria for LT at our center. We analyzed and compared the etiology, outcome, prognosis, and survival rates of patients between the transplantation (LT) group and the non-transplantation (N-LT) group., Results: AHF was due to viral hepatitis in 25 patients (52.1%; hepatitis B virus in 22), drug or toxic reactions in 14 (29.2%; acetaminophen in 6), Wilson disease in 4 (8.3%), unknown reasons in 3 (6.3%), and miscellaneous conditions in 2 (4.2%). In the LT group, 36 patients (7 underwent living donor LT, and 29 cadaveric LT) had an average model for end-stage liver disease score (MELD) of 35.7. Twenty-eight patients survived with good graft function after a follow-up of 27.3+/-4.5 months. During the waiting time, 6 patients were treated with ALSS and 2 of them died during hospitalization. The 30-day, 12-month, and 18-month survival rates were 77.8%, 72.2%, and 66.7%, respectively. In the N-LT group, 12 patients had an average MELD score of 34.5. Four patients were treated with ALSS and all died during hospitalization. The 90-day and 1-year survival rates were only 16.7% and 8.3%, respectively., Conclusions: Hepatitis is the most prominent cause of AHF at our center. Most patients with AHF, who fulfill the Kings College Criteria for LT, did not survive longer without LT. ALSS did not improve the prognosis of AHF patients, but may extend the waiting time for a donor. Currently, LT is still the most effective way to improve the prognosis of AHF patients.

Background: Bile duct injury (BDI) is a severe complication that may arise during the surgical treatment of benign disease and a few patients will develop end-stage liver disease (ESLD) requiring a liver transplant (LT)., Objective: Analyse the experience using LT as a definitive treatment of BDI in Argentina., Patients and Methods: A national survey regarding the experience of LT for BDI., Results: Sixteen out 18 centres reported a total of 19 patients. The percentage of LT for BDI from the total number of LT per period was: 1990-94 = 3.1%, 1995-99 = 1.6%, 2000-04 = 0.7% and 2005-09 = 0.2% (P < 0.001). The mean age was 45.7 ± 10.3 years (range 26-62) and 10 patients were female. The BDI occurred during cholecystectomy in 16 and 7 had vascular injuries. One patient presented with acute liver failure and the others with chronic ESLD. The median time between BDI and LT was 71 months (range 0.2-157). The mean follow-up was 8.3 years (10 months to 16.4 years). Survival at 1, 3, 5 and 10 years was 73%, 68%, 68% and 45%, respectively., Conclusions: The use of LT for the treatment of BDI declined over the review period. LT plays a role in selected cases in patients with acute liver failure and ESLD., (© 2011 International Hepato-Pancreato-Biliary Association.)

Patients with acute liver failure are a particularly challenging group, with unique difficulties faced in treatment decisions. Life-saving therapy is available, but organ shortage, delays in transplantation, and complications in management result in a high mortality in this group of patients even after transplant. Any pharmacologic intervention that improved outcomes in this population of critically ill patients would be of great benefit. Based on available evidence, different scenarios of participation of HSCs in liver recovery are conceivable. Encouraging HSCs to differentiate into hepatocytes or supply paracrine and cellular level support to accelerate ongoing local repair mechanisms and assist a failing liver with inadequate mass and functional capacity might be directed to occur effectively in humans. Evidence within small animal models of liver injury and observations within the human population suggest that this might also be encouraged. The use of pharmacologic agents to mobilize hematopoietic stem cells is well established and effectively used in a different population of patients. As such, extending the use of these drugs, such as plerixafor, to the human population has a sound basis. However, there is a need for clarification of the mechanisms by which these cells exert their effect as well as which specific population of cells is involved in the regenerative process. To be clinically relevant in scenarios of acute liver failure, stem cell mobilizing strategies would have to impact survival when administered well after injury. Applications in other settings may also prove useful. Limits to liver resection exist where the size of the future liver remnant governs the extent of resection possible. Preexisting functional impairment may be restrictive, and strategies involving stem cells may assist the future liver remnant in both normal and functionally impaired livers. Benefit has already been reported from treatment with G-CSF in other injured tissues, including the injured myocardium and acutely injured kidney. However, as yet no clinical trial exists to assess the effects of stem cell mobilization in humans with acute liver failure. The familiarity in the use of and success demonstrated in the clinical and experimental use of plerixafor and G-CSF make exploration of hematopoietic stem cells as therapy in patients with acute liver failure appealing.

Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling played critical roles in the pathological features of liver failure. These studies should help redirect examination of pathophysiologic and therapeutic mechanisms in liver failure., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The prognosis of liver transplantation for neonates with fulminant hepatic failure (FHF) continues to be extremely poor, especially in patients whose body weight is less than 3 kg. To address this problem, we have developed a safe living donor liver transplantation (LDLT) modality for neonates. We performed LDLTs with segment 2 monosubsegment (S2) grafts for three neonatal FHF. The recipient age and body weight at LDLT were 13-27 days, 2.59-2.84 kg, respectively. S2 or reduced S2 grafts (93-98 g) obtained from their fathers were implanted using temporary portacaval shunt. The recipient portal vein was reconstructed at a more distal site, such as the umbilical portion, to have the graft liver move freely during hepatic artery (HA) reconstruction. The recipient operation time and bleeding were 11 h 58 min-15 h 27 min and 200-395 mL, respectively. The graft-to-recipient weight ratio was 3.3-3.8% and primary abdominal wall closure was possible in all cases. Although hepatic artery thrombosis occurred in one case, all cases survived with normal growth. Emergency LDLT with S2 grafts weighing less than 100 g can save neonates with FHF whose body weight is less than 3 kg. This LDLT modality using S2 grafts could become a new option for neonates and very small infants requiring LT., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Severe liver disease in pregnancy is generally considered to have a favorable prognosis. The limited data available have not yielded disease-specific prognostic criteria or guidance on who should undergo liver transplantation (LT). We retrospectively evaluated 54 admissions with pregnancy-related liver disease to (1) evaluate if any admission parameters were associated with death and/or transplantation and (2) identify maternal complications. Eighteen had acute fatty liver of pregnancy and 32 had hypertension/eclampsia related disease. Seven patients (13%) died and four (7%) underwent LT. Survival rates were 43/48 if not listed for LT and 4/6 if listed. Of the four transplanted, three survived. Patients who died and/or underwent LT were more likely to have encephalopathy (p = 0.04) and hyperlactaemia (p = 0.03). Serum lactate was the best discriminant (ROC AUC 0.84). An admission lactate greater than 2.8mg/dL had 73% sensitivity and 75% specificity for predicting death or LT. The addition of encephalopathy to this parameter increased sensitivity and specificity to 90% and 86%, respectively. The King's College criteria were not effective in predicting outcome. This study confirms the overall favorable prognosis in pregnancy-related liver failure but indicates that elevated lactate levels in the presence of encephalopathy best identify patients at greatest risk of death or LT., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)