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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.)

BACKGROUND Wilson's disease (WD) manifesting as acute liver failure (ALF) is a life-threatening condition, and spontaneous recovery is rare. Diagnostic scores like the alkaline phosphatase elevation/total bilirubin elevation ratio and aspartate aminotransferase/alanine aminotransferase ratio can distinguish WD from other ALF etiologies. Liver transplantation plays a major role in treating these patients, and the revised Wilson Index is useful in patient selection for this procedure. The aim of this study was to evaluate diagnostic scores, treatments, and outcomes of a large cohort of patients with WD-ALF. MATERIAL AND METHODS Twenty adult patients of a historical cohort admitted from January 2001 to December 2017 were prospectively observed. Demographic, clinical, laboratory, and radiology data, and treatment, time on the waiting list for liver transplantation, and outcomes were recorded. RESULTS No diagnostic laboratory scores were 100% positive in patients with WD-ALF. Cut-off values for the alkaline phosphatase/total bilirubin ratio and aspartate aminotransferase/alanine aminotransferase ratio were met by 65.0% and 80.0% of patients, respectively. All patients met at least 1 criterion for high risk of death (Nazer or revised Wilson Index) and qualified for liver transplantation. In 9 patients, albumin dialysis was used before surgery. Survival after liver transplantation was 85.0% and 74.4% after 1 month and 1 year, respectively. CONCLUSIONS Further research on a novel diagnostic score in WD-ALF is warranted. Adult patients suspected to have WD as the cause of ALF should be treated in the referral liver transplantation unit. Liver transplantation makes long-term survival possible for patients with this critical illness.

Young children listed for liver transplant have high waitlist mortality (WL), which is not fully predicted by the PELD score. SRTR database was queried for children < 2 years listed for initial LT during 2002-17 (n = 4973). Subjects were divided into three outcome groups: bad (death or removal for too sick to transplant), good (spontaneous improvement), and transplant. Demographic, clinical, listing history, and laboratory variables at the time of listing (baseline variables), and changes in variables between listing and prior to outcome (trajectory variables) were analyzed using random forest (RF) analysis. 81.5% candidates underwent LT, and 12.3% had bad outcome. RF model including both baseline and trajectory variables improved prediction compared to model using baseline variables alone. RF analyses identified change in serum creatinine and listing status as the most predictive variables. 80% of subjects listed with a PELD score at time of listing and outcome underwent LT, while ~70% of subjects in both bad and good outcome groups were listed with either Status 1 (A or B) prior to an outcome, regardless of initial listing status. Increase in creatinine on LT waitlist was predictive of bad outcome. Longer time spent on WL was predictive of good outcome. Subjects with biliary atresia, liver tumors, and metabolic disease had LT rate >85%, while >20% of subjects with acute liver failure had a bad outcome. Change in creatinine, listing status, need for RRT, time spent on LT waitlist, and diagnoses were the most predictive variables., (© 2020 Wiley Periodicals LLC.)

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.)

Dengue is a common viral infection, especially in tropical countries, and it is a well-known cause of acute liver failure. The effects on the liver range from a mild illness to acute liver failure. Dengue-related acute liver failure has a high mortality rate, and the role of liver transplant in such cases has been less studied, due to the rapid progression and often associated multiorgan dysfunction in severe cases. Here, we report the first living donor liver transplant for an acute liver failure due to dengue. Although liver transplant is not the choice of treatment for sick patients, timely intervention in specific patients may have a role.

Extensive infiltration of M2 macrophages plays a crucial role in repairing acute liver failure (ALF), however, the molecular pathways whereby mesenchymal stem cells (MSCs) induce M2 macrophage polarization remains unknown. We investigated the molecular pathways involved in MSC-induced M2 polarization and describe the potential therapeutic effects of M2 macrophages on ALF. The expression of M2 macrophage markers was significantly increased after M0 macrophages were co-cultured with MSCs in vitro. MSCs induced M2 macrophage polarization by activating STAT6, whereas a STAT6 inhibitor significantly inhibited the expression of M2 macrophage polarization markers (IL-4, CD163, TGF-β, IL-10 and Arg-1). Finally, M2 macrophages significantly reduced the secretion of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from injured hepatocytes. These results demonstrated that MSCs induced M2 macrophage polarization by activating STAT6, and that M2 macrophages increased the expression of anti-inflammatory factors to alleviate ALF., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs)., Methods: All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study., Results: During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred., Discussion: EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed., (Copyright © 2020 by The American College of Gastroenterology.)

Severe liver failure, including acute liver failure and acute-on-chronic liver failure, is associated with high mortality, and many patients die despite aggressive medical therapy. While liver transplantation is a viable treatment option for liver failure patients, a large proportion of these patients die given the shortage in the liver donation and the severity of illness, leading to death while waiting for a liver transplant. Extracorporeal liver support devices, including molecular adsorbent recirculating system (MARS), have been developed as bridge to transplantation (bridge for patients who are decompensating while waiting for liver transplantation) and bridge to recovery (for whom recovery is deemed reasonable). In addition to its uses in acute liver failure and acute-on-chronic liver failure, the MARS system has also been applied in various clinical settings, such as drug overdosing and poisoning and intractable cholestatic pruritus refractory to pharmacological treatment. This review aims to discuss the controversies, potential benefits, practicalities, and disadvantages of using MARS in clinical practice., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Deoxyguanosine kinase (DGUOK) deficiency is one of the causes of the hepatocerebral form of mitochondrial depletion syndrome (MDS). It is characterized by an early onset of liver failure with concomitant neurological deterioration. In the current literature, there are only few reports regarding long-term observation of children with DGUOK deficiency. Liver transplantation (LTx) is controversial due to extrahepatic involvement and unpredictable outcome., Methods: Five patients (2 boys) from 4 different families with hepatocerebral MDS associated with DGUOK mutations diagnosed with liver failure were treated in our hospital between 2010-2019., Results: In all children clinical symptoms developed within the first days of live and hypoglycemia (hypoketotic), conjugated hyperbilirubinemia (cholestasis), severe lactic acidosis, and coagulopathy were observed. Two neonates had low birth-weight for gestational age and failed to thrive. Mild neurological involvement as hypotonia was observed in all children. Three children died at the age of 2, 6 months and 6,5 months of age, respectively, due to end-stage liver failure. In one case, LTx was not considered, in two patients (sisters) parents did not agree to this procedure. LTx was subsequently performed in two patients at the age of 6 and 7 months, respectively, one from deceased, and one from living related donor, in both before the final confirmation of DGUOK mutations. One boy died 2 months after LTx due to post-LTx procedure-related complications; one is still alive with 3years of follow-up, with good liver function and mild neurological disturbances. The diagnosis of DGUOK deficiency was confirmed by biallelic DGUOK mutations detection. Equally, patients were compound heterozygotes (three cases) and homozygotes (two cases). Three known molecular variants, including regulatory substitutions (c.1A>G, c.3G>A) and in-frame insertion (c.813&#95;814insTTT) were identified., Conclusions: Prognosis in patients with DGUOK deficiency is generally poor. Based on a review of the literature and our experience liver transplantation in selected patients with DGUOK mutation does not appear to be contraindicated, especially in those without or with minimal neurologic abnormalities., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome., Approach and Results: Among 47 PALF study participants, 12 IAMs collected ≤6 days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8 + ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n = 10), medium (n = 15), and low IAM (n = 22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P < 0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8 mg/dL, P < 0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P = 0.002); no deaths were reported. In an independent validation cohort (n = 71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile., Conclusion: Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression., (© 2020 by the American Association for the Study of Liver Diseases.)

Spontaneous survival rates in acute liver failure (ALF) are vastly improved by liver transplantation (LT). However, the value of induction agents beyond steroids continues to be debated. To understand the potential benefit of different induction regimens in the ALF population, we compared overall survival of recipients undergoing LT in the United States for ALF. Using the Scientific Registry of Transplant Recipients, we assessed the impact of induction immunosuppression (IS) in a cohort of 3754 first-time LT recipients with a diagnosis of ALF from 2002 to 2018. Induction IS therapy was grouped into steroid-only induction, use of antithymocyte globulin (ATG), or interleukin 2 receptor antibody. Other regimens were excluded from analysis. Survival analysis was estimated via Cox proportional hazards models and expressed as hazard ratios (HRs). In LT for ALF, the use of induction agents beyond steroids is increasingly frequent over the last 2 decades. The use of ATG is associated with worse overall survival, even after adjusting for donor and recipient factors, with HR of 1.24 (95% confidence interval, 1.00-1.53; P = 0.05). An elevated serum creatinine, recipient and donor age, and Black ethnicity, were all associated with reduced survival, whereas maintenance IS with calcineurin inhibitors (CNIs) was associated with improved survival. Although adjunct induction therapy has become more common, our analysis shows that compared with a steroid-only induction regimen, the addition of ATG is associated with worse overall survival after LT for ALF. CNI maintenance was highly protective, suggesting that an IS strategy focusing on corticosteroid-only induction followed by CNI maintenance may offer the best overall survival rate., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background: Acute liver failure is a rare and serious disease. Acute liver failure may be paracetamol-induced or non-paracetamol-induced. Acute liver failure not caused by paracetamol (acetaminophen) has a poor prognosis with limited treatment options. N-acetylcysteine has been successful in treating paracetamol-induced acute liver failure and reduces the risk of needing to undergo liver transplantation. Recent randomised clinical trials have explored whether the benefit can be extrapolated to treat non-paracetamol-related acute liver failure. The American Association for the Study of Liver Diseases (AASLD) 2011 guideline suggested that N-acetylcysteine could improve spontaneous survival when given during early encephalopathy stages for patients with non-paracetamol-related acute liver failure., Objectives: To assess the benefits and harms of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, in people with non-paracetamol-related acute liver failure., Search Methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (searched 25 June 2020), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 6) in The Cochrane Library, MEDLINE Ovid (1946 to 25 June 2020), Embase Ovid (1974 to 25 June 2020), Latin American and Caribbean Health Science Information database (LILACS) (1982 to 25 June 2020), Science Citation Index Expanded (1900 to 25 June 2020), and Conference Proceedings Citation Index - Science (1990 to 25 June 2020)., Selection Criteria: We included randomised clinical trials that compared N-acetylcysteine at any dose or route with placebo or no intervention in participants with non-paracetamol-induced acute liver failure., Data Collection and Analysis: We used standard methodological procedures as described in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CIs). We quantified statistical heterogeneity by calculating I 2 . We assessed bias using the Cochrane risk of bias tool and determined the certainty of the evidence using the GRADE approach., Main Results: We included two randomised clinical trials: one with 183 adults and one with 174 children (birth through age 17 years). We classified both trials at overall high risk of bias. One unregistered study in adults is awaiting classification while we are awaiting responses from study authors for details on trial methodology (e.g. randomisation processes). We did not meta-analyse all-cause mortality because of significant clinical heterogeneity in the two trials. For all-cause mortality at 21 days between adults receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (N-acetylcysteine 24/81 (29.6%) versus placebo 31/92 (33.7%); RR 0.88, 95% CI 0.57 to 1.37; low certainty evidence). The certainty of the evidence was low due to risk of bias and imprecision. Similarly, for all-cause mortality at one year between children receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (25/92 (27.2%) versus 17/92 (18.5%); RR 1.47, 95% CI 0.85 to 2.53; low certainty evidence). We downgraded the certainty of evidence due to very serious imprecision.  We did not meta-analyse serious adverse events and liver transplantation at one year due to incomplete reporting and clinical heterogeneity. For liver transplantation at 21 days in the trial with adults, there was inconclusive evidence of effect (RR 0.72, 95% CI 0.49 to 1.06; low certainty evidence). We downgraded the certainty of the evidence due to serious risk of bias and imprecision. For liver transplantation at one year in the trial with children, there was inconclusive evidence of effect (RR 1.23, 95% CI 0.84 to 1.81; low certainty of evidence). We downgraded the certainty of the evidence due to very serious imprecision.   There was inconclusive evidence of effect on serious adverse events in the trial with children (RR 1.25, 95% CI 0.35 to 4.51; low certainty evidence). We downgraded the certainty of the evidence due to very serious imprecision.  We did not meta-analyse non-serious adverse events due to clinical heterogeneity. There was inconclusive evidence of effect on non-serious adverse events in adults (RR 1.07, 95% CI 0.79 to 1.45; 173 participants; low certainty of evidence) and children (RR 1.19, 95% CI 0.62 to 2.16; 184 participants; low certainty of evidence). None of the trials reported outcomes of proportion of participants with resolution of encephalopathy and coagulopathy or health-related quality of life. The National Institute of Health in the United States funded both trials through grants. One of the trials received additional funding from two hospital foundations' grants. Pharmaceutical companies provided the study drug and matching placebo, but they did not have input into study design nor involvement in analysis., Authors' Conclusions: The available evidence is inconclusive regarding the effect of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, on mortality or transplant rate in non-paracetamol-induced acute liver failure. Current evidence does not support the guideline suggestion to use N-acetylcysteine in adults with non-paracetamol-related acute liver failure, nor the rising use observed in clinical practice. The uncertainty based on current scanty evidence warrants additional randomised clinical trials with non-paracetamol-related acute liver failure evaluating N-acetylcysteine versus placebo, as well as investigations to identify predictors of response and the optimal N-acetylcysteine dose and duration., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Post-transplant liver fibrosis (PTLF) is a common and severe complication in liver recipients. In this study, we assessed the impact of donor liver genetics on the development of PTLF. A total of 232 patients undergoing liver transplantation were included. Twenty-two single nucleotide polymorphisms (SNPs) associated with liver fibrosis were analyzed. Univariate analysis revealed seven donor SNPs to be associated with PTLF. In a multivariate analysis, independent risk factors of PTLF were genetic variation of donor GRP78 rs430397 (OR = 8.99, p = 0.003), GSTP1 rs1695 (OR = 0.13, p = 0.021), miRNA-196a rs12304647 (OR = 16.01, p =0.001), and TNF-α rs1800630 (OR = 79.78, p = 0.001); blood tacrolimus levels at maintenance > 7 ng/ml (OR =7.48, p <0.001); and post-transplant diabetes mellitus (OR = 7.50, p = 0.001). A predictive model that included donor SNPs showed better prognostic ability for PTLF than a model with only clinical parameters (AUROC: 0.863 vs 0.707, P < 0.001). Given that donor gene SNPs are associated with an increased risk of PTLF, this model integrated with donor gene polymorphisms may help clinicians predict PTLF.

Background: The effects of delayed graft function on long-term kidney allograft outcomes are poorly defined among simultaneous liver and kidney transplant recipients., Methods: We analyzed data of all simultaneous liver and kidney recipients transplanted at the University of Wisconsin between 2010 and 2017. Risk factors for the development of delayed graft function, kidney graft failure, and patient mortality were outcomes of interest., Results: There were a total of 60 simultaneous liver and kidney recipients; 28 (47%) had delayed graft function. After adjustment for multiple variables, we found that pretransplant dialysis >6 weeks (hazard ratio [HR] = 5.6, 95% CI: 1.23-25.59, P = .02), pretransplant albumin <3 g/dL (HR = 5.75, 95% CI: 1.76-16.94, P = .003), and presence of pretransplant diabetes (HR = 2.5, 95% CI: 0.97-4.77, P = .05) were significantly associated with delayed graft function. Multivariate analysis showed that pretransplant albumin <3 (HR = 4.86, 95% CI: 1.07-22.02, P = .02) was associated with a higher risk of all-cause kidney allograft failure, whereas the duration of delayed graft function (HR = 1.07 per day, 95% CI: 1.01-1.14, P = .01) was associated with a higher risk of death-censored kidney allograft failure. The presence of delayed graft function was not associated with all-cause or death-censored kidney or liver allograft failure. Similarly, the presence of delayed graft function was not associated with patient mortality., Conclusion: The incidence of delayed graft function was high in simultaneous liver and kidney recipients. However, with appropriate management, delayed graft function may not have a negative impact on patient or kidney allograft survival.

Pediatric ALF is rare but life-threatening and may require urgent transplantation. In low and middle-income countries, access to transplantation is limited, deceased organ donation rates are low, and data on outcomes scarce. The Wits Donald Gordon Medical Centre, in Johannesburg, is one of only two centers in South Africa that perform pediatric liver transplant. We describe the etiology, clinical presentation, and outcomes of children undergoing liver transplant for ALF at our center over the past 14 years. We performed a retrospective chart review of all children undergoing liver transplantation for ALF from November 2005 to September 2019. Recipient data included demographics, clinical and biochemical characteristics pretransplant, post-operative complications, and survival. We conducted descriptive data analysis and used the Kaplan-Meier method for survival analysis. We performed 182 primary pediatric liver transplants. Of these, 27 (15%) were for ALF, mostly from acute hepatitis A infection (11/27;41%). Just over half of the grafts were from living donors (15/27;56%), and five grafts (5/27;19%) were ABO-incompatible. The most frequent post-transplant complications were biliary leaks (9/27;33%). There were two cases of hepatic artery thrombosis (2/27;7%), one of whom required re-transplantation. Unadjusted patient and graft survival at one and 3 years were the same, at 81% (95% CI 61%-92%) and 78% (95% CI 57%-89%), respectively. At WDGMC, our outcomes for children who undergo liver transplantation for ALF are excellent. We found workable solutions that effectively addressed our pervasive organ shortages without compromising patient outcomes., (© 2020 Wiley Periodicals LLC.)

We present a case of pediatric ALF, secondary to hepatic HL, who underwent a successful ABOi living donor liver transplant. We believe this is the first such case reported in academic literature. HL with liver involvement is extremely rare and is not considered an indication for transplantation. The 12-year-old, male patient presented with a viral illness prodrome, and parvovirus was detected in pre-transplant laboratory cultures. He received an ABOi living donor liver graft followed by a course of plasma exchange and rituximab after which standard immunosuppression was used. The HL was diagnosed on hepatic biopsy post-transplant. Subsequently, the patient commenced six cycles of R-CHOP chemotherapy. During chemotherapy, we stopped tacrolimus and mycophenolate mofetil. Immunosuppression was maintained with corticosteroids in-between cycles. The patient is alive and reports good quality of life 1-year post-transplant. The HL is in remission. During the post-operative period, the patient experienced four episodes of neutropenia, a bile leak, and gram-negative sepsis. One episode of acute rejection has been treated. Although we did not initially transplant the patient for ALF secondary to HL, its subsequent diagnosis and the patient's response to management raises many issues that warrant consideration. While the findings from a single case cannot be generalized, this could be a "proof of concept" for liver transplantation in hepatic HL. We hope it will facilitate discussions and potentially expand therapeutic options available to this very small group patients., (© 2020 Wiley Periodicals LLC.)

Background: Treatment options for patients presenting with life-threatening splanchnic ischemia, including that of the intestine and liver, could previously only receive salvage surgery and attempted medical revascularization. We propose that urgent liver transplantation (LT) for acute liver failure (ALF) due to massive liver necrosis should be considered as a life-saving treatment. We successfully performed urgent living donor LT for nonocclusive hepatic ischemia accompanied by nonocclusive mesenteric ischemia (NOMI)., Case: An 11-month-old boy with biliary atresia whose jaundice was re-elevated after Kasai portoenterostomy underwent cysto-jejunostomy. Three hours after the uneventful operation, tachycardia, hypotension, and unconsciousness suddenly occurred. Computed tomography revealed whole-liver and massive splenic and focal intestinal ischemia without any vessel occlusion. Urgent LT was performed on postoperative day 3 because intensive therapies, including prostaglandin E1 administration, blood transfusion, and continuous hemodiafiltration, were not effective and the patient had developed life-threatening bradycardia and hypotension. Intraoperative findings included whole-liver necrosis and splenic ischemia and segmental ileal necrosis without any vessel thrombus. LT and necrotic intestinal resections by end-to-end anastomosis were performed. Massive liver necrosis with Gram-positive cocci was histopathologically identified, indicating bacterial translocation due to NOMI. The post-LT course was uneventful, and the neurologic outcomes were uncomplicated., Conclusions: Urgent LT was successfully completed for ALF with NOMI. LT is the sole treatment for the refractory ALF, and undelayed determination is important to rescue., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: It is well known that local complications, such as avascular necrosis and arthrosis can develop after surgery for developmental dysplasia of the hip (DDH). Thus far, systemic complications that may develop in such cases have not been identified in the literature. This study is the first case series to evaluate acute liver failure (ALF) development after DDH surgery in pediatric patients., Patients and Methods: Six patients, five female and one male, who underwent DDH surgery were selected for this study. Perioperative fasting time, laboratory values, treatments, histopathological evaluations, and prognoses after ALF in these patients were evaluated retrospectively., Results: All the patients were administered paracetamol and sevoflurane in therapeutic doses. The patients were referred postoperatively to our pediatric emergency department after 5 ± 1.67 days (range = 3-7 days) on average. The average perioperative fasting time was 9.3 ± 0.82 hours (range = 8-10 hours). Due to the very high aminotransferases and use of paracetamol, intravenous N-acetylcysteine was administered alongside supportive treatments to all the patients. After liver transplantation, two of three patients with grade 3 encephalopathy, died in the early postoperative period. Histopathological evaluations of the three patients' explants were compatible with toxic hepatitis due to paracetamol., Conclusions: Paracetamol is a commonly used analgesic after pediatric surgery. The therapeutic dose of paracetamol remains uncertain in children who have been fasting for a long time and have been exposed to hepatotoxic drugs due to previous surgery. In conclusion, caution should be exercised in the use of paracetamol in children with DDH who will undergo surgery, and careful perioperative clinical and laboratory monitoring for ALF is essential.

BACKGROUND Drug-induced liver failure is a rare complication of pregnancy and occasionally requires liver transplantation. However, fulminant liver failure arising from in vitro fertilization (IVF) therapy involving progestogens (e.g. dydrogesterone) is extremely rare and has not been reported in pregnancy. Furthermore, dydrogesterone-mediated hepatic dysfunction has not previously necessitated liver transplantation and is usually conservatively managed. We report the first Australian case of a pregnant woman with delayed fulminant liver failure and in utero fetal death requiring a liver transplant from dydrogesterone use. CASE REPORT A 35-year-old multiparous (G₅P₂) woman presented with painless jaundice and transaminitis (alanine aminotransferase and aspartate aminotransferase of 2800 U/L and 2990 U/L respectively). She was pregnant at 14 weeks' gestation after successful IVF in Thailand four months before involving dydrogesterone therapy. She was diagnosed with delayed, subfulminant liver failure arising from previous dydrogesterone use. Initially, she was not encephalopathic and conservative management strategies were instituted. Her hepatic dysfunction progressed and she deteriorated clinically with encephalopathy, necessitating an emergent liver transplantation. Fetal death was confirmed in utero four days before transplantation. A combined orthotopic liver transplant and hysterotomy with fetal evacuation were performed without complication. CONCLUSIONS Fulminant liver failure in pregnancy due to idiosyncratic drug reactions are rare. Dydrogesterone may cause significant, albeit delayed, liver dysfunction in pregnancy necessitating the need for liver transplantation. Early recognition of progressive liver failure despite best supportive care efforts should prompt early considerations for liver transplantation. Delays in liver transplantation with prolonged hyperbilirubinemia and coagulopathy may exacerbate fetal death in utero.

Objectives: Acute drug-induced liver failure is a rare indication for liver transplant. There is only one case of flupirtine-induced liver failure requiring transplant in the literature. In February 2018, the European Medicines Agency issued a withdrawal of approval for flupirtine medication in European countries as a result of the risk of acute liver failure., Materials and Methods: The aim of this study was a German-wide collection of data regarding patients with liver transplant as a result of flupirtine-associated liver failure., Results: A total of 9 patients received transplants. All patients were women with a mean age of 43 years. Indication for flupirtine medication was musculoskeletal symptoms and migraine headache. The medication was taken over a period of approximately 3 months. All patients developed progressive acute liver failure, and no patient had previous chronic liver disease or cirrhosis. The mean laboratory Model for End Stage Liver Disease score for the patients was 31 ± 7 at time of transplant. Eight of the 9 patients were listed as "high urgency" for transplant. After transplant, they had an uneventful course with a prolonged mean intensive care unit stay of 13 ± 8.7 days. The whole hospitalization time was 43 ± 21 days., Conclusions: This is the largest published series of patients who received liver transplant after a drug-induced acute liver failure from flupirtine medication.

Background: Pediatric acute liver failure is a rare, life-threatening illness. Mushroom poisoning is a rare etiology. For patients with irreversible pediatric acute liver failure, liver transplantation is the ultimate lifesaving therapy. However, it is difficult to determine the optimal timing of transplantation. Here, we present a case of pediatric acute liver failure due to mushroom poisoning in northeastern China. He was treated with liver transplantation and recovered. To our knowledge, there are few reports about liver transplantation for pediatric acute liver failure caused by mushroom poisoning in mainland China., Case Presentation: The patient was a previously healthy 9-year-old boy who gradually developed nausea, vomiting, jaundice and coma within 5 days after ingesting mushrooms. He was diagnosed with mushroom poisoning and acute liver failure. He was treated with conservative care but still deteriorated. On the 7th day after poisoning, he underwent LT due to grade IV hepatic encephalopathy. Twenty days later, he recovered and was discharged. A review of the literature revealed that the specific criteria and optimal timing of transplantation remain to be determined., Conclusions: Patients with pediatric acute liver failure should be transferred to a center with a transplant unit early. Once conservative treatment fails, liver transplantation should be performed.

Background: Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease with grim prognosis., Objective: Our aim was the analysis of prognostic factors, long-term outcome and risk of tumour development in SSC-CIP compared with primary sclerosing cholangitis (PSC) patients., Methods: Retrospective analysis between 2008 and 2018., Results: One hundred and eleven patients with SSC-CIP and 408 PSC patients were identified. Median orthotopic liver transplantation (OLT)-free survival was 16 months for SSC-CIP and 147 months for PSC ( p  < 0.001). OLT was performed in 18/111 SSC-CIP compared with 166/408 PSC patients ( p  < 0.001). Malignant tumours were detected in 17.9% of PSC patients (73/408) compared with 2.7% (3/111) in SSC-CIP ( p  < 0.001). In multivariate Cox regression analysis low levels of C-reactive protein (hazard ratio 4.687 (95% confidence interval (CI) 1.144-19.199, p  = 0.032) were significantly associated with a prolonged survival whereas higher age (hazard ratio 0.488 (95% CI 0.23-1.038), p  = 0.062) showed a trend for shorter survival in SSC-CIP. For PSC malignancies (hazard ratio 0.42 (95% CI 0.313-0.575), p  < 0.001) and higher age (hazard ratio 0.709 (95% CI 0.544-0.922), p  = 0.01) were associated with a shorter OLT-free survival., Conclusion: SSC-CIP is characterized by acute onset of liver disease and poor prognosis but with lower tumour incidence compared with PSC.

The etiology and prognosis of acute liver failure (ALF) remains unknown in a significant proportion of cases. Signs of autoimmunity may be present, but no consistent pattern has been observed. We aimed to analyze if pretransplant immunological findings, human leukocyte antigen (HLA) haplotypes, and clinical features among patients with an unknown etiology differ from those of autoimmune or other known etiologies. We also analyzed whether such signs impact posttransplant biopsy findings or complications. All adult ALF patients undergoing liver transplantation (LT) in Finland during 1987-2015 were followed to 2016. Data were collected from the LT registry, pathology database, and patient records. A total of 124 patients were included in the analysis. Study subgroups were acute autoimmune hepatitis (AIH; n = 25), known non-AIH etiology (n = 54), and unknown etiology (n = 45). The unknown etiology group differed from the known non-AIH group with regard to the following pretransplant autoimmunity-associated features: positive perinuclear anti-neutrophil cytoplasmic antibodies (36% versus 8%; P = 0.02) and higher mean immunoglobulin A (IgA; 3.2 ± 1.7 versus 2.1 ± 1.4, P = 0.006) and immunoglobulin G (IgG; 12.7 ± 4.3 versus 8.5 ± 3.6, P = 0.001). AIH-associated HLA haplotypes B8, DR3, and B8DR3 were more common in the AIH group (40%, 44%, and 36%, respectively) and in the unknown group (29%, 33%, and 29%, respectively) than in the known non-AIH group (11%, 17%, and 11%, respectively) or in the Finnish general population (17%, 18%, and 8%, respectively). However, these findings had no association with protocol biopsies, extrahepatic autoimmune diseases, or survival. Patients with ≥ 1 rejection episode had higher pretransplant IgA (3.7 ± 2.3 versus 2.6 ± 1.2; P = 0.02) and IgG (16.4 ± 10.2 versus 12.4 ± 6.8; P = 0.03) than those without rejections. Autoimmunity-associated pretransplant laboratory findings and HLA haplotypes were common in ALF of unknown etiology, but they showed minimal predictive value for posttransplant biopsy findings, clinical complications, or survival., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Introduction: Toxic acute liver failure can be fatal even after liver transplantation. Since there are data only in young rats, the aim of our study was to verify the effectiveness of the increase of oxygen to the liver by partial portal vein arterialization (PPVA) in elderly rats with acute liver failure induced by carbon tetrachloride (CCl 4 ) intoxication., Methods: Twenty elderly (30 months) Sprague-Dawley rats underwent a CCl 4 intoxication (5 mL/kg). Animals were divided after 24 hours (n = 10 per group) to either undergo PPVA (G1, treated group) or be untreated (G2, control group). PPVA consisted of a shunt between the left renal artery and splenic vein after nephrectomy and spelnectomy. The G2 group animals underwent nephrectomy and splenectomy only. The 10-day survival was evaluated. Before euthanasia, blood samples from the portal vein were detected for blood gas analysis. Liver injury was evaluated by the serum alanine aminotransferase (ALT) and prothrombin time levels. Histology was done to evaluate the liver necrosis. Hepatocyte regeneration was assessed by the mitotic index at immunohistochemistry., Results: The PPVA has resulted in a significant increase in the oxygen partial pressure and saturation in portal blood. A survival improvement at 10 days was registered in the PPVA-treated rats (90% vs 30%; P = .0065). After 24 hours from intoxication, ALT was high in both groups. A rapid decrease of ALT was observed in G1 as compared to G2. At the same time, livers showed a severe centrolobular necrosis. In the suviving G2 rats, a moderate necrosis was present, while only a mild necrosis was observed in the G1 rats. An higher mitotic index was detected in rats treated with PPVA., Conclusions: In our experimental study, the presence of oxygenated blood in the portal venous system following the PPVA procedure had positive effects on liver regeneration and rats' survival. The PPVA treatment had beneficial effects in elderly rats., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acute liver failure is a rare condition consisting of abrupt and extensive hepatocyte injury, leading to significant liver dysfunction associated with a high mortality. Liver transplantation is the most effective treatment in severe cases. The most common cause of acute liver failure in Western countries is drug-induced liver injury caused by prescription drugs and herbal and dietary supplements. Thermogenics, or fat burners, are a category of dietary supplements that claim to increase the resting metabolic rate, leading to weight loss. There are previous reports of acute liver failure associated with specific thermogenic formulations. We report the case of a 36-year-old male patient who developed jaundice 7 days after he started taking a thermogenic dietary supplement (Thermo Gun), with progressive deterioration of hepatic function and development of hepatic encephalopathy 19 days after the beginning of the symptoms. He had a Model for End-Stage Liver Disease score of 38 and fulfilled 4 of the King's College Criteria for poor prognosis in patients with acute liver failure. He underwent liver transplantation, receiving a graft from a cadaveric donor, and is alive with good liver graft function 2 years after the transplant. No possible causes for acute liver injury were identified other than the use of the supplement, which contained N-acetyl-L-tyrosine; 1,3,7-trimenthylxanthine; white willow; and 1-hydroxypholedrine. We found no previous reports in the literature of acute liver failure associated with those particular substances. This manuscript is compliant with the Helsinki Congress and the Istanbul Declaration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.)

Objective: Hyperammonaemia contributes to complications in acute liver failure (ALF) and may be treated with continuous renal replacement therapy (CRRT), but current practice is poorly understood., Design: We retrospectively analysed data for baseline characteristics, ammonia concentration, CRRT use, and outcomes in a cohort of Australian and New Zealand patients with ALF., Setting: All liver transplant ICUs across Australia and New Zealand., Participants: Sixty-two patients with ALF., Main Outcome Measures: Impact of CRRT on hyperammonaemia and patient outcomes., Results: We studied 62 patients with ALF. The median initial (first 24 h) peak ammonia was 132 μmol/L (interquartile range [IQR], 91-172), median creatinine was 165 μmol/L (IQR, 92-263) and median urea was 6.9 mmol/L (IQR, 3.1-12.0). Most patients (43/62, 69%) received CRRT within a median of 6 hours (IQR, 2-12) of ICU admission. At CRRT commencement, three-quarters of such patients did not have Stage 3 acute kidney injury (AKI): ten patients (23%) had no KDIGO creatinine criteria for AKI, 12 (28%) only had Stage 1, and ten patients (23%) had Stage 2 AKI. Compared with non-CRRT patients, those treated with CRRT had higher ammonia concentrations (median, 141 μmol/L [IQR, 102-198] v 91 μmol/L [IQR, 54-115]; P = 0.02), but a nadir Day 1 pH of only 7.25 (standard deviation, 0.16). Prevention of extreme hyperammonaemia (> 140 μmol/L) after Day 1 was achieved in 36 of CRRT-treated patients (84%) and was associated with transplant-free survival (55% v 13%; P = 0.05)., Conclusion: In Australian and New Zealand patients with ALF, CRRT is typically started early, before Stage 3 AKI or severe acidaemia, and in the presence hyperammonaemia. In these more severely ill patients, CRRT use was associated with prevention of extreme hyperammonaemia, which in turn, was associated with increased transplant-free survival.

Ulipristal has recently been suspected to be hepatotoxic by the European Medicines Agency but the evidence base for hepatotoxicity is sparse. This is a brief formal report of a patient administered ulipristal for 6-8 weeks and who developed acute liver failure leading to liver transplantation. The explanted liver showed extensive hepatocyte necrosis and inflammation compatible with drug-induced liver injury and cirrhosis. The usual causes of acute hepatitis and cirrhosis were eliminated. There were no other potential causative drugs. This case suggests that ulipristal may cause acute hepatitis, with pre-existing cirrhosis probably contributing to the severity of liver injury observed in this case. Ulipristal prescribers must remain vigilant and monitor liver function in their patients., (Copyright © 2020 Elsevier Masson SAS. 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.)

Liver regenerates following surgical removal and after drug-induced liver injury (DILI). However, most of the mechanisms of liver regeneration were identified using partial hepatectomy (PHX) model rather than using DILI models. We compared mechanisms of liver regeneration following PHX and after acetaminophen (APAP) overdose, a DILI model, using transcriptomic approach. Kinetics of hepatocyte proliferation and global gene expression profiles were studied in male C57BL/6J mice either subjected to PHX or following APAP overdose. Liver regeneration was much more synchronized after PHX as compared to APAP overdose. Transcriptomics analysis revealed activation of common upstream regulators in both models including growth factors HGF, EGF and VEGF; and cytokines IL6 and TNFα. However, magnitude of activation and temporality was significantly differed between the two models. HGF and VEGF showed similar activation between PHX and APAP but activation of EGF was significantly stronger in the APAP model. Activation of IL6 and TNFα transcriptional programs was delayed but remarkably higher in APAP. These dissimilarities could be attributed to inherent differences in the two models including significant injury and inflammation exclusively in the APAP model. This study highlights need to study mechanisms of liver regeneration after DILI separately from the mechanisms of regeneration PHX., 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 © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Transfusion protocols are not well-studied for pediatric patients with acute liver failure (ALF). This study evaluates the utility of an international normalized ratio (INR)-based transfusion threshold for these patients., Methods: Forty-four ALF pediatric patients from 2009 to 2018 were reviewed and divided into two groups: (a) a threshold group including patients between 2009 and 2015 who were transfused for an INR above 3.0, per institutional policy (n = 30), and (b) a post-threshold group including patients after 2015 through 2018 who were transfused based on clinical judgment (n = 14). Preoperative INRs, preoperative transfusions, intraoperative transfusions, early reoperation, renal function, graft function and deaths were compared., Results: Liver failure severity was similar between threshold and post-threshold groups. Threshold patients had a lower average INR prior to transplantation, 2.8 (range 1.8-3.8) vs 4.4 (range 2.1-9.0), respectively (P = .01). Twenty-six threshold patients (87%) received preoperative FFP compared with seven post-threshold patients (50%, P = .0088). Two threshold patients (7%) received preoperative cryoprecipitate compared with five post-threshold patients (36%, P = .014). The incidence of pre-transplant bleeding, operative transfusions, and 1-year patient and graft survival did not differ significantly., Conclusion: Clinical judgment vs an INR-based threshold for transfusions did not increase perioperative complications in children with ALF., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

Cell therapy and tissue engineering (TE) are considered alternative therapeutic approaches to organ transplantation. Since cell therapy approaches achieved little success for liver failure treatment, liver TE is considered a more promising alternative. In this study, we produced a liver tissue equivalent (called "liver-derived extracellular matrix scaffold [LEMS]-Patch") by co-culture of human bone marrow stromal cells, human umbilical vein endothelial cells, and a hepatoma cell line, Huh7, within an artificial three-dimensional liver-extracellular matrix scaffold. The results showed significant increase in the liver-specific gene expression and hepatic functions, in terms of albumin (ALB) and fibrinogen secretion, urea production, and cytochrome inducibility in the LEMS-Patch compared to controls. In addition, transplanted LEMS-Patch was successfully incorporated into the recipient liver of acute liver failure mice and produced human ALB. Consequently, our data demonstrated that the generated LEMS-Patch could be used as a good platform for functional improvement of hepatic cells in vitro and in vivo.

Background: The concept of organ transplantation as treatment for complex genetic conditions, including Wolcott-Rallison syndrome (WRS), continues to show promise. Liver transplantation is essential for survival of patients with WRS, and pancreas transplantation cures their type I diabetes mellitus., Methods: The recipient, a 3-year-old girl weighing 14 kg at the time of transplantation, suffered from major complications of WRS, including repetitive liver failure episodes and poorly controlled diabetes. The patient underwent a nonacute, combined, simultaneous liver and pancreas transplantation from a pediatric donor without using the en bloc technique., Results: Well-preserved graft functions at 2-year follow-up with normal liver and pancreas function., Conclusions: This is the first case report of simultaneous liver and pancreas transplantation as treatment of WRS in a small child in Europe. Two-year follow-up demonstrates that organ transplantation can halt life-threating recurrent liver failure episodes and cure type 1 diabetes.

Drug-induced liver injury (DILI) is the most common cause of acute liver failure (ALF) in Western countries. Without liver transplantation, the mortality rate for ALF approaches greater than 80%. Acetaminophen-related ALF may be associated with a rapid progression but fortunately has a high chance for spontaneous survival compared with idiosyncratic DILI-related ALF. Several prognostic scoring systems for severe DILI have been developed to aid clinicians in selecting patients who require urgent liver transplantation. Patients who undergo liver transplantation for ALF are at risk for early graft loss and death and should be closely followed., (Copyright © 2019 Elsevier Inc. All rights reserved.)