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Background: Although acute hepatitis caused by varicella zoster virus mostly develops in immunocompromised patients, hyperacute liver failure is very rare. To our knowledge, there are no previous reports on liver transplant patients., Methods: We report the first case of fatal hyperacute liver failure due to varicella zoster virus immediately after living-donor liver transplantation without cutaneous lesions and review the literature., Result: The present case exhibited rapid development and progression of acute liver failure from postoperative days 11-13, despite being seropositive for varicella zoster virus but unvaccinated and on immunosuppression before transplantation. Especially in solid organ transplantation, only six cases of severe acute liver failure that included hepatic encephalopathy and/or impaired consciousness and sudden extremely high (> 4000 U/L) serum aspartate aminotransferase levels have been reported in heart, lung, and kidney transplant patients., Conclusions: Early diagnosis of hyperacute liver failure due to varicella zoster virus is challenging because the disease progresses rapidly and skin lesions are absent., (© 2024 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Although the outcomes of living donor liver transplantation (LDLT) for pediatric acute liver failure (PALF) have improved, patient survival remains lower than in patients with chronic liver disease. We investigated whether the poor outcomes of LDLT for PALF persisted in the contemporary transplant era., Methods: We analyzed 193 patients who underwent LDLT between December 2000 and December 2020. The outcomes of patients managed in 2000-2010 (era 1) and 2011-2020 (era 2) were compared., Results: The median age at the time of LDLT was 1.2 years both eras. An unknown etiology was the major cause in both groups. Patients in era 1 were more likely to have surgical complications, including hepatic artery and biliary complications (p = 0.001 and p = 0.013, respectively). The era had no impact on the infection rate after LDLT (cytomegalovirus, Epstein-Barr virus, and sepsis). The mortality rates of patients and grafts in era one were significantly higher (p = 0.03 and p = 0.047, respectively). The 1- and 5-year survival rates were 76.4% and 70.9%, respectively, in era 1, while they were 88.3% and 81.9% in era 2 (p = 0.042). Rejection was the most common cause of graft loss in both groups. In the multivariate analysis, sepsis during the 30 days after LDLT was independently associated with graft loss (p = 0.002)., Conclusions: The survival of patients with PALF has improved in the contemporary transplant era. The early detection and proper management of rejection in patients, while being cautious of sepsis, should be recommended to improve outcomes further., (© 2024 Wiley Periodicals LLC.)

Background: Hepatic progenitor cell (HPC) activity and regenerative process that follows pediatric acute liver failure (PALF) is still not well understood. This clinicopathological study was thus conducted with an aim to study the correlation of liver histology and HPC activity with outcomes in PALF., Methods: All PALF patients with available hepatic histological specimens were included and specimens were analyzed for hepatocyte loss, HPC activity [using cytokeratin (CK) 7, CK19, sex-determining region Y-related high mobility group box(SOX)9 and epithelial cell adhesion molecule (EpCAM)], hepatocyte proliferation (using Ki67), and hepatocyte senescence (using p53 and p21)., Results: Ninety-four children were included: 22 (23.4%) survived with native liver (SNL) (i.e., the good outcome group) while rest (i.e., the poor outcome group) either died [33%, 35.1%] or received liver transplant (LT) [39%, 41.5%]. When compared to subjects with poor outcomes, those in the SNL group exhibited significantly less severe hepatocyte loss, fewer HPC/hpf, more proliferating hepatocytes, and less senescent hepatocytes (p < .05). Increasing severity of hepatocyte loss (adjusted OR: 9.95, 95% CI: 4.22-23.45, p < .001) was identified as an independent predictor of poor outcome. Eighty percent children with >50% native hepatocyte loss had poor outcome within 10 days of hospitalization., Conclusion: In PALF, more severe hepatocyte loss, higher number of HPC activation, lesser number of proliferating hepatocytes, and greater number of senescent hepatocytes are associated with a poor outcome. Loss of >50% hepatocytes is an independent predictor of poor outcome in PALF., (© 2023 Wiley Periodicals LLC.)

Background: Acute liver failure (ALF) is a component of multisystem organ failure that causes severe liver dysfunction in patients without underlying chronic liver disease. The patients with ALF are prone to have infections, including bacteremia. However, studies of the infectious impact for post liver transplantation (LT) in pediatric ALF are limited. We aimed to evaluate our current practice for pediatric LT cases of ALF with preoperative bacteremia., Methods: The records of all patients under 18 years old undergoing LT for ALF in our center from November 2005 to December 2021 were collected. They were divided into two groups: those with a preoperative bloodstream infection (BSI) and those without (NBSI). We compared the preoperative status and also reviewed the details of the BSI group. Intraoperative course and postoperative outcomes were also compared., Results: There were 19 BSI patients and 66 NBSI patients. One BSI case was detected on the day of LT. This patient had no changes in vital signs and general condition. After evaluation and therapeutic intervention by pediatric infectious disease specialists, LT was performed on the same day. Five cases developed septic shock at the time of detection of BSI. All BSI patients were in stable condition on the operation day with proper interventions. There were no significant differences in mortality and hospital stay between both groups., Conclusions: LT might be able to be performed for pediatric ALF even with positive blood cultures. In addition, appropriate therapeutic intervention by specialists and patient's stable condition before LT are essential., (© 2023 Wiley Periodicals LLC.)

Background: Pediatric acute liver failure (PALF) is an emergency, necessitating prompt referral and management at an experienced liver transplant center. Social determinants of health (SDOH) drive healthcare disparities and can affect many aspects of disease presentation, access to care, and ultimately clinical outcomes. Potential associations between SDOH and PALF outcomes, including spontaneous recovery (SR), liver transplant (LT) or death, are unknown. This study aims to investigate how SDOH may affect PALF and therefore identify areas for intervention to mitigate unrecognized disparities., Methods: A retrospective, single-center cohort was analyzed and then compared and validated with data from the multicenter National Institutes of Health PALF Study Group. The single-center review included 145 patients admitted with PALF using diagnostic codes. Medical records were reviewed to extract patient demographics, family structure, inpatient social worker assessments, and clinical outcomes. Data were stratified by outcome., Results: This analysis determined that level of family support (p = .02), caretaker employment (p = .02), patient age, race, and language (p = .01) may impact clinical outcomes. Specifically, the cohort of children that died had the largest proportion of non-English speaking patients with limited support systems and parents who worked full-time. Conversely, patients who underwent LT more often belonged to English-speaking families with a homemaker and extensive support systems., Conclusion: This study suggests that SDOH impact PALF outcomes and highlights patient populations facing additional challenges during an already complex healthcare emergency. These associations may indicate unconscious biases held by transplant teams when evaluating waitlist candidacy, as well as barriers to healthcare access. Strategies to better understand the broader applicability of our findings and, if confirmed, efforts to mitigate social disparities, may improve clinical outcomes in PALF., (© 2024 Wiley Periodicals LLC.)

Background: Pediatric acute liver failure (PALF) is one of the most demanding emergencies in hepatology, intensive care, and for transplant team. This report describes the clinical pattern, diagnostic and therapeutic modalities in children with ALF considered at risk of death without liver transplantation, basing on a long-term experience of the pediatric transplant center., Materials and Methods: Between 1990 and 2022, 104 children aged 7 days-17 years (median 8 years), with body weight 3.1 to 77 kg (median 32 kg), were qualified for LT due to ALF, and finally 81 (78%) of them were transplanted (9% of all 899 LT performed in children in the same period)., Results: A total of 23 children were not transplanted: 15 (14.4%) died while awaiting transplantation. In 8 (7.7%) patients liver function recovered. Before transplantation 45 (43.3%) children developed circulatory failure, in 66 (63.5%) mechanical ventilation was necessary, 18 patients presented acute kidney injury (17.3%), and encephalopathy higher than stage I was present in 60 (57.7%) patients. In 63 children, various kidney/liver assist procedures were performed: CVVHD (continuous veno-venous hemodiafiltration in 22 (21.2%) patients, albumin dialysis (MARS; molecular adsorbent recirculating system) in 39 (37.5%) patients, therapeutic plasma exchange (TPE) in 13 (12.5%) patients. Twenty (24.7%) children died after LT including 15 (18.5%) in the early posttransplant period, and 5 (6.1%) in the late follow-up., Conclusions: Treatment of children with ALF in the peritransplant period is very difficult and require an experienced, multidisciplinary team. Despite continued advances in the care of children with ALF, patient survival remains lower than for elective indications for liver transplantation, and timely qualification and transplantation still are the most important factors of survival of these children., (© 2023 Wiley Periodicals LLC.)

Background & Aims: Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF., Methods: We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality., Results: About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7)., Conclusion: Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs., (© 2023 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF., Methods: Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS)., Results: Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n = 114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients with true-IND ALF versus patients with indeterminable ALF (29.8% vs. 27.2%), with almost half of the patients requiring liver transplant (42.1% vs. 45.7%)., Conclusion: We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Acute liver failure (ALF) is characterized by hepatic encephalopathy (HE) often due to intracranial hypertension (ICH). The risk/benefit-balance of intraparenchymal pressure catheter monitoring is controversial during ALF., Aims: Perform an evaluation of transcranial Doppler (TCD) use in patients with ALF listed for emergency liver transplantation., Material and Methods: Single center retrospective cohort study including all patients registered on high emergency LT list between 2012 and 2018. All TCD measurements performed during ICU stay after listing and after LT (when performed) were recorded. TCD was considered abnormal when pulsatility index (PI) was >1.2., Results: Among 106 patients with ALF, forty-seven (44%) had a TCD while on list. They had more severe liver and extrahepatic organ failure. When performed, TCD was abnormal in 51% of patients. These patients more frequently developed ICH events (45% vs. 13%, p = .02) and more frequently required increase in sedative drugs and vasopressors. While 22% of patients with normal TCD spontaneously survived, all of those with abnormal TCD died or were transplanted (p = .02). All transplanted patients who had abnormal exams normalized their TCD within 2 (1-2) days after LT., Conclusion: TCD may be a useful non-invasive tool for ICH detection and management, then guide sedation withdrawal., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Neurological impairment is not rare in infants with acute liver failure (ALF). This study aimed to investigate the perioperative risk factors for neurological impairment following liver transplantation (LT) in infantile ALF., Methods: Retrospective analysis was performed in infants who were younger than 1 year with ALF who subsequently underwent LT at our hospital between January 2005 and December 2016. Patients were considered to have neurological impairment if the Pediatric Cerebral Performance Category score was between 2 and 5 at the age of 6 years. A comparison between the groups of infants with and without neurological impairment was performed, and factors with p < .10 in the comparison were analyzed using univariate logistic regression analysis for neurological impairment., Results: Twenty-six infants survived until 6 years of age, and 31% (8/26) of them had neurological impairment. Patients with neurological impairment were significantly younger in age at ALF onset, had significantly higher pre-LT bilirubin and prothrombin time/international normalized ratio, and stayed significantly longer in the intensive care unit than those without neurological impairment. Total bilirubin (odds ratio (OR) = 1.12, 95% confidence interval (CI) 1.02-1.22, p = .012), indirect bilirubin (OR = 1.10, 95% CI 1.01-1.20, p = .025), direct bilirubin (OR = 1.22, 95% CI 1.01-1.47, p = .040), and age in month at ALF (OR = 0.76, 95% CI 0.58-0.999, p = .049) showed significant association with neurological impairment., Conclusions: High pre-LT peak bilirubin value and younger age at ALF onset can be perioperative risk factors for neurological impairment after LT in infantile ALF., (© 2023 Wiley Periodicals LLC.)

The emergence of coronavirus disease 19 (COVID-19) has significantly disrupted liver transplantation worldwide. Despite significant, collective experience in treating liver transplant recipients with COVID-19, there remains a paucity of data to guide the management of transplant candidates with acute COVID-19 who require urgent transplantation. We present the case of an otherwise well, 39-year-old female presenting for urgent liver transplantation for acute liver failure secondary to hepatitis B, with concomitant acute, mild COVID-19 due to Omicron BA.2. COVID-19 antivirals were not administered pre-transplant as the potential risk of hepatotoxicity precipitating further deterioration of liver function was not felt to outweigh the small, potential benefit of antiviral therapy. No effective SARS-CoV-2 monoclonal antibodies were available; however, the patient was previously vaccinated against SARS-CoV-2 with evidence of anti-spike antibodies at the time of COVID-19. Transplantation surgery and recovery were uncomplicated with no progression of COVID-19 post-transplant, hospital discharge was at day 14. At 30 days post-transplant the patient had recovered, with normal liver function and SARS-CoV-2 was not detectable on nasopharyngeal PCR. While the safety of transplantation of patients with acute COVID-19 cannot be assured by a single case, ours highlights the complex decision-making process undertaken and competing priorities that need to be balanced when assessing patients with acute COVID-19 who require urgent transplantation., (© 2022 Wiley Periodicals LLC.)

Background: Although overall survival of ALF has improved, neurological restoration after recovery from ALF may not always be satisfactory. The purpose of this study was to investigate the occurrence and possible causes of NI in children with ALF following LT., Methods: We retrospectively examined all children younger than 16 years old with ALF who subsequently underwent LT at our center between January 2005 and December 2016. NI was assessed in December 2016 using the six-point Pediatric Cerebral Performance Category score and was defined as any increase in the score., Results: There were 62 children with median age 10 months (quartile range 5-34). The etiology of ALF was indeterminate in 47 children (75.8%). The median duration from admission to LT was 5.5 days (quartile range 4-7), and 96.8% (60/62) received living donor LT. The overall survival was 83.9% (52/62) in a median follow-up period of 4.2 years. Mild-to-moderate NI was observed in 23.1% (12/52) of the survivors. Possible causes of NI were underlying systemic disease (n = 3), perioperative brain lesion (n = 2), and unclassified (n = 7). All seven patients with unclassified NI were less than 12 months old. The unclassified NI causes were presumed to be ALF, its perioperative care, and the vulnerable infant brain., Conclusions: NI in children with ALF following LT was not rare and should be prevented. Further investigations are required to clarify the characteristics of the patients with unclassified NI., (© 2022 Wiley Periodicals LLC.)

Acute liver failure is life-threatening and has to be treated by liver transplantation urgently. When deceased donors or ABO-compatible living donors are not available, ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) becomes the only choice. How to prepare ABO-I LDLT urgently is an unsolved issue. A quick preparation regimen was designed, which was consisted of bortezomib (3.5 mg) injection to deplete plasma cells and plasma exchange to achieve isoagglutinin titer ≤ 1: 64 just prior to liver transplantation and followed by rituximab (375 mg/m 2 ) on post-operative day 1 to deplete B-cells. Eight patients received this quick preparation regimen to undergo ABO-I LDLT for acute liver failure from 2012 to 2019. They aged between 50 and 60 years. The median MELD score was 39 with a range from 35 to 48. It took 4.75 ± 1.58 days to prepare such an urgent ABO-I LDLT. All the patients had successful liver transplantations, but one patient died of antibody-mediated rejection at post-operative month 6. The 3-month, 6-month, and 1-year graft/patient survival were 100%, 87.5%, and 75%, respectively. In conclusion, this quick preparation regimen can reduce isoagglutinin titers quickly and make timely ABO-I LDLT feasible for acute liver failure., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Mitochondrial respiratory chain disorder (MRCD) can cause acute liver failure (ALF), which may necessitate liver transplantation (LT). However, MRCD is often difficult to diagnose before LT and the indications of LT are controversial due to the likelihood of progressive neurological disease. The present study further characterized the patient population and described the outcomes., Methods: Thirteen patients who underwent LT for MRCD from November 2005 to May 2020 were enrolled in this study., Results: Six of 13 MRCD patients were diagnosed with a mitochondrial inner membrane protein 17-related mitochondrial DNA depletion syndrome (MTDPS). Overall, nine survived with a median follow-up of 1.8 years (IQR, 1.3-5.1 years); four died within 2 years. In the long-term, seven survivors showed no progression of hypotonia after LT and attended a normal kindergarten or primary school. Neurological abnormalities were observed in two survivors, including vison loss related to Leber's hereditary optic neuropathy in one patient and psychomotor retardation related to Leigh syndrome in the other. Three non-survivors after LT were diagnosed with MTDPS and died of severe pulmonary hypertension, which had developed at 8, 9, and 18 months after LT (n=1 each). The remaining patient died of postoperative respiratory infection with respiratory syncytial virus., Conclusion: The long-term results support the performance of LT in patients with MRCD, although a genetic diagnosis is preferable for determining the accurate indications for LT in these patients. Furthermore, care should be taken to avoid complications due to mitochondrial dysfunction during the long-term follow-up., (© 2021 Wiley Periodicals LLC.)

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.)

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.)

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.)

Late allograft fibrosis in LT recipients can cause graft dysfunction and may result in re-transplantation. TE is a non-invasive tool for the assessment of liver fibrosis. We aimed to evaluate the prevalence of allograft fibrosis in pediatric LT recipients, identify factors associated with allograft fibrosis, and determine the diagnostic value of TE, compared to histology. All children who underwent LT for ≥3 years were included. TE was performed for LSM in all patients. LSM of ≥7.5 kPa was considered as abnormal and suggestive of allograft fibrosis. Percutaneous liver biopsy was performed when patients had abnormal LSM and/or abnormal LFTs. Histological fibrosis was diagnosed when METAVIR score ≥F1 or LAF scores ≥1. TE was performed in 43 patients and 14 (32.5%) had abnormal LSM suggestive of allograft fibrosis. Histological fibrosis was identified in 10 of the 15 patients (66.7%) who underwent percutaneous liver biopsy and associated findings included chronic active HBV infection (n = 3), and late acute rejection (n = 3). Multivariate analysis showed that graft age was significantly associated with allograft fibrosis (OR = 1.22, 95% CI: 1.05-1.41, P = 0.01). In conclusion, late allograft fibrosis is common in children undergoing LT for ≥3 years and associated with graft age. HBV infection and late acute rejection are common associated findings. Abnormal TE and/or LFTs may guide physicians to consider liver biopsy for the detection of late allograft fibrosis in LT children., (© 2019 Wiley Periodicals, Inc.)

Hepatitis A virus (HAV) can cause acute liver failure (ALF). This study compares outcomes between liver transplantation (LT) for HAV-related ALF (HAV-ALF) and LT for hepatitis B virus (HBV)-related ALF (HBV-ALF). Of 3616 adult LTs performed between January 2005 and December 2014, we performed LT for HAV-ALF recipients (n = 29) and LT for HBV-ALF recipients (n = 34). HAV-ALF group included 18 males and 11 females with mean age of 33.1 years. Graft survival rates in HAV-ALF and HBV-ALF were 65.5% and 88.0% (1 year) and 65.5% and 84.0% (5 years) (P = .048). Patient survival rates in HAV-ALF and HBV-ALF were 69.0% and 88.0% (1 year) and 69.0% and 84.0% (5 years) (P = .09). Multivariate analyses demonstrated that acute pancreatitis and HAV recurrence were independent risk factors of graft and patient survival. Post-transplant outcome was poorer in patients with HAV-ALF than in those with HBV-ALF. This weakens LT's appropriateness in HAV-ALF patients with pancreatitis. HAV recurrence after LT for HAV-ALF is common and often fatal; thus, HAV recurrence should be monitored vigilantly, beginning early post-transplant., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The allocation of liver transplants to patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) with multi-organ failure who are admitted in ICU remains controversial due to their high post-transplant mortality rate and the absence of identified mortality risk factors., Methods: We performed a single-center retrospective cohort study to determine the post-transplant mortality rate of patients with ALF and ACLF requiring ICU care prior to liver transplant (LT) and identified pretransplant factors of post-transplant mortality., Results: Eighty-four patients (29 with ALF and 55 with ACLF) received a liver transplant while they were hospitalized at the ICU. Their mean model for end-stage liver disease (MELD) score was 41, and their mean sequential organ failure assessment (SOFA) was 15 the day before transplant. The overall 1-year survival rate was 66%. In multivariate analysis, pretransplant lactate level and acute respiratory distress syndrome (ARDS) were the only two independent factors associated with post-transplant mortality. The absence of ARDS and a pretransplant lactate level< 5 mmol/L led to the identification of a subgroup of ICU patients with a good 1-year post-transplant survival (>80%)., Conclusions: Low lactatemia lactate level and the absence of ARDS could be useful criteria in selecting those patients in ICU who could be eligible for liver transplant., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although chronic hepatitis C is still the leading indication for liver transplantation (LT) in the United States and Europe, acute liver failure caused by hepatitis C is distinctly uncommon and transplantation for fulminant hepatitis C virus (HCV) has not been documented in the United States. We present a case report of fulminant hepatic failure caused by genotype 2a/c HCV not only treated with LT but also complicated by severe, rapid recurrence of HCV within 6 days of transplantation. The risk factor for the initial infection was likely sexual, and there were no explanations for acute hepatitis post-transplant other than recurrent hepatitis C. Treatment with all-oral direct antiviral agents was swiftly initiated during the index hospitalization, leading to resolution of the acute hepatitis and resulting in sustained virologic response. It can only be speculated whether this was an infection with the JFH-1 strain or another similarly virulent genotype 2a/c HCV infection., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report a rare case of acute liver failure from acute hepatitis E virus (HEV) in a non-pregnant woman without comorbidities who survived after liver transplantation. The source was likely consumption of partially cooked pig liver. HEV genotype 3 is the second most common genotype causing acute hepatitis E in developed countries. Fulminant hepatitis E rarely occurs without a risk factor, as in our patient. Vigilant monitoring for chronic hepatitis E in post-transplant immunocompromised patients is needed., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Active tuberculosis (TB) is commonly considered a contraindication for liver transplantation (LT). However, in patients with TB who develop acute liver failure (ALF) due to toxicity induced by anti-tubercular treatment (ATT), LT could be the only opportunity for treatment. The aim of this study was to evaluate the feasibility of LT in this scenario., Methods: We described 2 cases and comprehensively reviewed the literature finding 26 cases of LT performed in patients having a concomitant active TB and liver failure secondary to ATT toxicity., Results: TB was classified as pulmonary in 18/26 (69%), nodal in 3/26 (11%) TB cases, while the remaining 5/26 cases included disseminated, pleural, renal, ovarian, and vertebral TB localization (1 case each). ATT following LT consisted mainly of isoniazid or rifampin (RIF)-sparing regimens and included primarily fluoroquinolones and ethambutol. Rejection episodes and liver toxicity were reported in 19% and 8% of patients respectively. Graft rejection was more frequent among patients treated with RIF-containing regimens (P<.001). Mortality rate was 15% after a median follow up of 12 months. In only one case was death attributed to uncontrolled TB infection., Conclusion: Our findings suggest that LT is an effective therapeutic option for patients with active TB developing ALF following ATT and should be considered for patients failing medical treatment., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Toxoplasmosis may be transferred by organ transplantation. The most common clinical presentation is with multisystem disease, although isolated ocular toxoplasmosis has been described. Many centers have suggested that universal use of co-trimoxazole prophylaxis obviates the need for specific Toxoplasma testing. We report a case of donor-acquired ocular toxoplasmosis after liver transplantation despite co-trimoxazole prophylaxis. The diagnosis was confirmed by Toxoplasma polymerase chain reaction assay in conjunction with seroconversion. The fact that the infection was donor acquired was confirmed by serological mismatch and the absence of sporozoite-specific antigen antibody in the recipient., (© 2016 The Authors. Transplant Infectious Disease Published by John Wiley & Sons Ltd.)

The outcome of LTx in pediatric patients with FHF of unknown etiology remains inferior to that of LTx in pediatric patients with cholestatic diseases. A higher incidence of steroid-resistant severe rejection has been increasingly recognized among the responsible factors. We assessed the efficacy of the administration of steroids and PGE1 via PVI in the management of LTx for FHF in pediatric patients. In our early cohort (1995-2007), seven patients who underwent LTx for FHF of unknown etiology were treated with conventional immunosuppressive therapy (calcineurin inhibitor and a steroid). Seven of eight grafts (one patient underwent re-LTx) sustained CV and/or CPV associated with ACR, and four patients died of a graft failure or infectious complications that were associated with the treatment for rejection. Of note, the pathological incidence of CV/CPV was significantly higher in recipients with FHF of unknown etiology than in recipients with biliary cholestatic disease during the same study period (87.5% vs. 13.7%, p < 0.00001). From 2008, three patients underwent LTx for cryptogenic FHF with PVI and conventional IS. PVI was well tolerated, and no relevant severe complications were observed. More strikingly, the patients who received PVI overcame biopsy-proven immunological events and are all currently doing well with excellent graft function after more than five yr. We conclude that PVI is technically safe and effective for preventing severe rejection in pediatric patients who undergo LTx for FHF of unknown etiology and that it does not increase the risk of fatal infectious complications., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pediatric LDLT using donors with unfavorable vascular anatomy is challenging in terms of donor safety, and complexity of reconstruction in the recipient. We describe an innovative technique of hepatic venous outflow reconstruction involving the recipient RHV, in the presence of a rudimentary RHV in the donor. The postoperative course of the donor and recipient was uneventful with satisfactory venous outflow in both. This technique avoided the use of prosthetic material, an important consideration given the recipient age and requirement for growth. This shows that donors previously considered unsuitable for donation can be utilized safely as long as principles of vascular anastomosis are adhered to. Moreover, it highlights that innovation is sometimes necessary to avoid compromise in donor safety., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

NH is the most common identifiable cause of ALF in the neonate. LT is the definitive treatment for neonates with NH who have failed medical therapy. Our aim was to determine the outcomes of LT in infants with NH. Patients (less than one yr of age) with NH who were listed for LT and patients who underwent LT between 1994 and 2013 were identified from the UNOS database for analysis. Risk factors for death and graft loss were analyzed by multivariate logistic regression. Thirty-eight infants with NH with a total of 43 transplants were identified. One- and five-yr patient and graft survival were 84.2%, 81.6%, 71.1%, and 68.4%, respectively. The outcomes for NH were not significantly different when compared to the same age-matched recipients with other causes of ALF. There were no statistically significant risk factors identified for graft loss or death. Ninety infants with NH were listed for LT. Reasons for removal included transplanted (49%), death (27%), too sick to transplant (7%), and improved status (13%). LT for infants with NH has a high rate of graft loss and death; however, outcomes are comparable to the same age-matched recipients with other causes of ALF., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The most common identifiable causes of acute liver failure in pediatric patients are infection, drug toxicity, metabolic disease, and autoimmune processes. In many cases, the etiology of acute liver failure cannot be determined. Acute leukemia is an extremely rare cause of acute liver failure, and liver transplantation has traditionally been contraindicated in this setting. We report a case of acute liver failure in a previously healthy 15-yr-old male from pre-B-cell acute lymphoblastic leukemia. He underwent liver transplantation before the diagnosis was established, and has subsequently received chemotherapy for pre-B-cell acute lymphoblastic leukemia. He is currently alive 31 months post-transplantation. The published literature describing acute lymphoblastic leukemia as a cause of acute liver failure is reviewed., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The prognosis of fulminant hepatic failure (FHF) depends on the etiology and reversibility. In this study, we identified the etiological difference of FHF in Korea and analyzed the prognostic factors after liver transplantation (LT) for FHF., Methods: We retrospectively reviewed 42 patients with FHF who underwent LT from April 1999 to April 2011 at Samsung Medical Center, Seoul, Korea. The patients were categorized into two groups according to the short-term result of LT, and perioperative profiles were compared to identify the short-term poor prognostic factors., Results: Unlike Western countries, there was no paracetamol-related FHF but herbal/folk medicines were the most frequent causes of FHF (26.2%). HAV-related FHF increased significantly and comprised the main portion of FHF with Herbal/folk medicines after 2005. Encephalopathy grade, onset time, pre-transplantation need of renal replacement, and ventilator treatment were significantly different between groups in univariate analysis. In multivariate analysis, pre-transplantation renal replacement treatment and hepatic encephalopathy grade IV were the independent prognostic factors after LT., Conclusions: The etiologies of FHF in Korea were different compared with Western reports. The requirement of renal replacement treatment and hepatic encephalopathy grade IV were identified as independent poor prognostic factors after LT for FHF in this study., (© 2012 John Wiley & Sons A/S.)

Segmental liver grafts from DCD in pediatric LT have been safely used even in acute liver failure situations. Furthermore, despite the risk of antibody-mediated acute rejection, some studies have also demonstrated the safety of ABO incompatible LT in infants. The use of such grafts can be beneficial by reducing the time on the transplant waiting list but they are more susceptible to initial dysfunction and there is a lack of enthusiasm to consider their use especially for an emergency LT as a life-saving procedure. In this short article, we describe the use and successful outcome in a neonate with fulminant acute liver failure secondary to neonatal hemochromatosis who received an ABO-incompatible reduced-size DCD graft., (© 2011 John Wiley & Sons A/S.)

Liver transplantation (LT) for very small recipients is challenging but in experienced centres, good results can be achieved. Despite the risk of antibody-mediated acute rejection, some studies have demonstrated the safety of ABO incompatible liver transplantation (ILT) in children and particularly in infants. The aim of our study was to describe the outcome of liver transplantation in infants <5 kg and the safety of using ILT in this group. All LT performed between 1991 and 2010 in children <5 kg were reviewed. Twenty-nine patients were included, five of whom had an ILT. Acute liver failure was encountered in 20 cases. The recipient age and weight at transplantation were respectively 63 days (range: 14-268 days) and 4 kg (range: 2.4-5 kg). The graft-to-recipient ratio was 6.1% (range 2.3-9%). An aortic conduit and delayed abdominal closure were used respectively in 76% and 81% of the procedures. The ABO compatible liver transplantation (CLT) and ILT groups were similar regarding recipient's demographics, graft types or technical transplantation data. The one- and five-yr patient and graft survival were respectively 62%, 62% and 62%, 57.9% with a median follow-up of 95 months. Vascular complications occurred in six cases (21.4%) and biliary complications were encountered in five patients (17%). Acute and chronic rejection developed respectively in 37% and 26% of the recipients. The five patients undergoing ILT are all alive without graft lost after a median follow-up of 34 months (range 7-55 months). When compared with the CLT group, no significant differences were found regarding patient or graft survival, vascular or biliary complications and rejection rates. In our experience, ILT in small infants has short and long term outcomes comparable to ABO-compatible grafts and excellent results can be achieved with a standard immunosuppressive protocol. To avoid mortality on the waiting list for neonatal recipients, ABO-incompatible liver grafts can be used safely., (© 2011 John Wiley & Sons A/S.)

Unlabelled: Liver transplantation (LT) is lifesaving for patients with Wilson disease (WD) presenting with fulminant hepatic failure (FHF) or chronic liver disease (CLD) unresponsive to treatment., Aim: To determine the outcome of LT in pediatric and adult patients with WD., Methods: United Network for Organ Sharing data on LT from 1987 to 2008 were analyzed. Outcomes were compared for patients requiring LT for FHF and CLD after 2002. Multivariate logistic regression was used to determine risk factors for death and graft loss., Results: Of 90,867 patients transplanted between 1987 and 2008, 170 children and 400 adults had WD. The one- and five-yr patient survival of children was 90.1% and 89% compared to 88.3% and 86% for adults, p = 0.53, 0.34. After 2002, 103 (41 children) were transplanted for FHF and 67 (10 children) for CLD. One- and five-yr patient survival was higher in children transplanted for CLD compared to FHF; 100%, 100% vs. 90%, 87.5% respectively, p = 0.30, 0.32. One- and five-yr patient survival was higher in adults transplanted for CLD compared to FHF; 94.7%, 90.1% vs. 90.3%, 89.7%, respectively, p = 0.36, 0.88. Encephalopathy, partial graft, and ventilator use were risk factors for death by logistic regression., Conclusion: LT is an excellent treatment option for patients with WD. Patients transplanted for CLD had higher patient survival rates than patients with FHF., (© 2010 John Wiley & Sons A/S.)

To date, no child has been reported to develop de novo CCA after liver transplantation although patients with transplants have a significantly higher risk of malignancy than the general population. CCA is extremely rare in the pediatric age group, seen mostly in patients with a history of choledochal cysts, Caroli's disease, or PSC. We report the first case of pediatric de novo CCA in the liver allograft 12 yr after liver transplantation., (© 2009 John Wiley & Sons A/S.)

LLS reduction has been frequently used in infants weighing <7 kg. Twenty recipients weighing <7 kg at the time of LDLT, median age 11.0 months and body weight 5.6 kg, were treated with an RLLS (n = 12) or LLS (n = 8) graft. Absolute indication of size reduction was that the estimated GRWR was >4.0%. Even if the preoperative GRWR was <4.0%, the RLLS graft was considered to ensure a size match. A flatfish-type LLS was preferred to a blowfish-type to make an RLLS graft for such a small infantile population. The RLLS recipients had significantly more flatfish-type grafts, while the LLS recipients had more blowfish-type grafts. Primary full-layer wound closure could be performed successfully in all LLS recipients, while in the RLLS group, two patients were forced to have partial skin closure. There were no graft losses related to graft compression. Reducing an LLS is a useful procedure to promote the comfortable accommodation of the graft in an infant weighing <7 kg. Flatfish-type LLS allowed more flexibility to make the suitable volume.

Children transplanted for ALF urgently require an optimal graft and have lower post-transplant survival compared with children transplanted for chronic liver disease. Over 10 yr, 33 consecutive children transplanted for ALF were followed. Demographics, encephalopathy, intubation, dialysis, laboratory values, graft type ABOI, XL (GRWR > 5%), DDSLT, LDLT and WLT were evaluated. Complications and survival were determined. ALF accounted for 33/201 (16.4%) of transplants during this period. Twelve of 33 received ABOI, five XL grafts, 18 DDSLT, and three LDLT. Waiting time pretransplant was 2.1 days. One- and three-yr patient survival in the ALF group was 93.4% and 88.9%, and graft survivals were 86.4% and 77.7%. Median follow-up was 1452 days. ABOI one- and three yr patient and graft survival in the ALF was 91.6% and 78.6%. No difference in graft or patient survival was noted in the ALF and chronic liver disease group or the ABOI and the ABO compatible group. A combination of ABO incompatible donor livers, XL grafts, DDSLT, LDLT and WLT led to a short wait time and subsequent graft and patient survival comparable to patients with non-acute disease.

Background: Rapid deterioration of consciousness is a critical situation for patients with fulminant hepatic failure (FHF). Bispectral (BIS) index was derived from electroencephalography parameters, primarily to monitor the depth of unconsciousness., Aim: To assess the usability of peritransplant BIS monitoring in patients with FHF., Methods: A prospective study using peritransplant BIS monitoring was performed in 26 patients with FHF undergoing urgent liver transplantation (LT)., Results: Pre-transplant Child-Pugh score was 12.2 +/- 1.0; model for end-stage liver disease score was 32.4 +/- 4.4; Glasgow coma score (GCS) was 9.9 +/- 1.3; and BIS index was 44.0 +/- 6.7. Pre-transplant sedation significantly decreased BIS index. After LT, all patients having endotracheal intubation recovered consciousness within one to three d and showed progressive increase in BIS index, which appeared slightly earlier and was more evident than the increase in derived GCS score. There was a significant correlation between BIS index and derived GCS scores (r(2) = 0.648). Timing of eye opening to voice was matched with BIS index of 66.3 +/- 10.4 and occurred 12.7 +/- 8.3 h after passing BIS index of 50., Conclusion: These results suggest that BIS monitoring is a non-invasive, simple, easy-to-interpret method, which is useful in assessing peritransplant state of consciousness. BIS monitoring may therefore be a useful tool during peritransplant intensive care for patients with FHF showing hepatic encephalopathy.

ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow-up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post-operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.

With increasing shortage of donor organs and changes in organ allocation systems, there is a considerable need for alternative or supportive techniques in the field of liver transplantation. Liver cell transplantation (LCT) is such an innovative technique that is especially promising for use in children, because it is less invasive than orthotopic liver transplantation (OLT). Two main indications exist: acute liver failure (ALF) and hepatic-based inborn errors of metabolism. Ten children with ALF underwent LCT so far. One patient recovered without OLT, five were successfully bridged to OLT, and four died. Clinical improvement like reduced hyperammonemia, improved coagulation, and regression of hepatic encephalopathy occurred in the majority of patients. For the treatment of inborn errors of metabolism, experience exists with Crigler-Najjar syndrome type 1 (CNS 1, n = 5) and urea cycle disorders (UCD, n = 6). All but two patients experienced metabolic stabilization for a mean period of 9.7 months, before the majority of children underwent OLT. Whereas transplant success in CNS 1 patients can be easily monitored by plasma bilirubin levels, it is much more difficult in UCDs, where many factors can contribute to clinical deterioration. Nevertheless, these individual therapeutic attempts of LCT yielded encouraging results, and prospective studies should be initiated.

The outcome of pediatric LT for FHF was shown to be poor in our center. To better understand such results, recipient and transplant parameters with a putative impact on post-transplant outcome were analyzed in LT for FHF. Between March 1984 and June 2002, 33 children with FHF received a primary liver allograft. The overall results in this series were studied with respect to pre-operative demographic and metabolic variables, peri-operative events, and outcome. Five-yr patient and graft survivals were 71% and 66%, respectively, with a retransplantation rate at 18%. Incidences of perioperative hemorrhage, of HAT and PVT were 14%, 8%, and 4%, respectively. Five-yr acute rejection-free survival rate was 55%. These data confirm the worse outcome following LT for FHF when compared with LT in elective, non-malignant indications such as BA; results in FHF could not be related to surgical or immunological complications in the post-transplant period and it is hypothesized that the MOF associated with FHF contributes to early post-transplant mortality which would justify special management, including aggressive renal and hepatic support.

Background: Tuberculosis (TB) infection in a liver transplantation candidate is not rare in China. There is little experience on how to manage the pre-existing TB infection in liver transplantation recipients. Aim. Patients with pre-existing pulmonary TB who received liver transplantation are described and the perioperative treatment is discussed., Methods: The treatment of 3 patients with pre-existing pulmonary TB infection who received liver transplantation was reviewed., Results: The patients were given nonstandard antituberculous therapy according to their reaction to the drugs. No evidence of TB infection relapse was discovered., Conclusion: Pre-existing TB infection should not be an absolute contraindication to orthotopic liver transplantation. The use of second-line antituberculous therapy is safe and effective for the treatment of TB infection in liver transplantation recipients.

The management of patients with pre-existing tuberculosis (TB) undergoing liver transplantation is challenging. Cautious immunosuppression is required to prevent reactivation of disease, and second-line anti-tuberculous treatment may be necessary to prevent graft hepatotoxicity. Furthermore, liver transplantation in the context of isoniazid-resistant TB has seldom been reported. We report on a 44-year-old man with recent isoniazid-resistant extra-pulmonary TB who developed subacute hepatic failure requiring emergency liver transplantation and treatment with second-line anti-tuberculous therapy. We demonstrate that patients who have pre-existing TB can be successfully treated with alternative anti-tuberculous medication while under immunosuppression post transplantation. Pre-existing TB, including resistant strains, should not be an absolute contraindication to liver transplantation.