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Background & Aims: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH., Methods: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability., Results: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018)., Conclusions: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF., Impact and Implications: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis., Trial Registration Number: #NCT02900443., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Interruption of the enterohepatic circulation is regarded as an effective way to treat patients with amatoxin poisoning. Nonetheless, its effectiveness has not yet been systematically evaluated. Therefore, we performed a systematic review to investigate the role of enterohepatic circulation on patient outcome and clinical laboratory values. We specifically sought to evaluate the effect of activated charcoal, which absorbs drugs and toxins in the gastrointestinal tract., Methods: A previously established database with data extracted from case reports and series from literature, supplemented with recent publications, was used. Patient characteristics, outcome, and laboratory values were evaluated., Results: We included 133 publications describing a total of 1,119 unique cases. Survival was 75 per cent in the control group ( n  = 452), whereas in the group treated with single or multiple doses of activated charcoal ( n  = 667) survival was 83 per cent ( P  < 0.001, odds ratio 1.89 [95 per cent confidence interval 1.40-2.56]). Furthermore, no difference in peak values of alanine aminotransferase and aspartate aminotransferase activities were observed, whereas peak values of total serum bilirubin concentration and international normalized ratio were statistically significantly reduced in patients treated with activated charcoal., Discussion: The ability of activated charcoal to enhance the elimination of amatoxin through interruption of the enterohepatic circulation offers a potentially safe and inexpensive therapy for patients in the post-absorptive phase., Limitations: Limitations include the potential for publication bias, the lack of universal confirmation of amatoxin concentrations, and the inability to directly measure enterohepatic circulation of amatoxin., Conclusion: Treatment with activated charcoal in patients with amatoxin poisoning was associated with a greater chance of a successful outcome. Additionally, activated charcoal was associated with a reduction in markers of liver function, but not markers of liver injury.

Background: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH., Methods: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness., Discussion: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines., Trial Registration: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021., (© 2024. The Author(s).)

Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1-2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h., Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1-2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740., Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9-15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6-8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9-46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively., Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation., Funding: University Medical Center Groningen, the Netherlands., Competing Interests: Vincent E. de Meijer reports a VENI research grant by the Dutch Research Council (NWO; grant #09150161810030), a Research grant from the Dutch Ministry of Economic Affairs (Health ∼ Holland Public Private Partnership grant #PPP-2019-024), and a Research grant from the Dutch Society for Gastroenterology (NVGE #01-2021), all outside the submitted work. Other authors declare that they have no competing interests., (© 2023 The Author(s).)

Background and Aims: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors., Methods: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk., Results: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development., Conclusions: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome., Impact and Implications: The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The impact of different immunosuppression regimes on the health-related quality of life (HRQoL) and the severity of fatigue in liver transplant recipients is largely unknown. We investigated the impact of a sirolimus-based regimen compared with a tacrolimus (TAC)-based regimen on the HRQoL and the severity of fatigue., Methods: In this multicenter, open-label, randomized, controlled trial, 196 patients were randomized 90 d after transplantation to (1) once daily normal-dose TAC or (2) once daily combination therapy of low-dose sirolimus and TAC. HRQoL was measured with the EQ-5D-5L questionnaire, the EQ-visual analog scale, and the severity of fatigue questionnaire Fatigue Severity Score (FSS). The EQ-5D-5L scores were translated to societal values. We examined the HRQoL and the FSS over the course of the study by fitting generalized mixed-effect models., Results: Baseline questionnaires were available for 87.7% (172/196) of the patients. Overall, patients reported the least problems in the states of self-care and anxiety/depression and the most problems in the states of usual activities and pain/discomfort. No significant differences in HrQol and FSS were seen between the 2 groups. During follow-up, the societal values of the EQ-5D-5L health states and the patient's self-rated EQ-visual analog scale score were a little lower than those of the general Dutch population in both study arms., Conclusions: The HRQoL and FSS were comparable in the 36 mo after liver transplantation in both study groups. The HRQoL of all transplanted patients approximated that of the general Dutch population, suggesting little to no residual symptoms in the long term after transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. Therefore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT., Methods: Patients after first LT were randomized to C2 or T0. tBPAR, patient- and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan-Meier survival analysis and log-rank test., Results: In intention-to-treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months ( p =0.104), and 21.9% vs. 9.7% at 6 and 12 months ( p =0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% ( p =0.049) and graft loss 23.8% vs. 9.4% ( p =0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% ( p ≤0.001), with no other differences in safety and tolerability., Conclusions: In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2., Competing Interests: BvH has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)

The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre-post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST ( p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization ( p = 0.001), whereas LDLT increased from 55% to 74% ( p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST ( p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment., Methods: A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects., Results: Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events., Conclusions: CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed., Competing Interests: ME Tushuizen has been an editorial board member of Journal of Clinical and Translational Hepatology since 2021, and B van Hoek has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2022 Authors.)

Background: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH., Methods: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks., Discussion: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases., Trial Registration: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016., (© 2022. The Author(s).)

Background and Aims: Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified., Methods: We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity., Results: We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality., Conclusion: Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.

Objectives: Thermal ablation (TA) is an established treatment for early HCC. There is a lack of data on the efficacy of repeated TA for recurrent HCC, resulting in uncertainty whether good oncologic outcomes can be obtained without performing orthotopic liver transplantation (OLTx). This study analyses outcomes after TA, with a special focus on repeat TA for recurrent HCC, either as a stand-alone therapy, or in relationship with OLTx., Methods: Data from a prospectively registered database on interventions for HCC in a tertiary hepatobiliary centre was completed with follow-up until December 2020. Outcomes studied were rate of recurrence after primary TA and after its repeat interventions, the occurrence of untreatable recurrence, OS and DSS after primary and repeat TA, and complications after TA. In cohorts matched for confounders, OSS and DSS were compared after TA with and without the intention to perform OLTx., Results: After TA, 100 patients (56·8%) developed recurrent HCC, of whom 76 (76·0%) underwent up to four repeat interventions. During follow-up, 76·7% of patients never developed a recurrence unamenable to repeat TA or OLTx. OS was comparable after primary TA and repeat TA. In matched cohorts, OS and DSS were comparable after TA with and without the intention to perform OLTx., Conclusions: We found TA to be an effective and repeatable therapy for primary and recurrent HCC. Most recurrences can be treated with curative intent. There are patients who do well with TA alone without ever undergoing OLTx., Key Points: • Recurrent HCC after primary TA can often be treated effectively with repeat TA. Survival after repeat TA is comparable to primary TA. • In matched cohorts, outcomes after TA with and without subsequent waitlisting for OLTx are comparable. • There are patients who do well for many years with primary and repeat TA alone; some despite multiple recurrences., (© 2022. The Author(s).)

Ex situ normothermic machine perfusion (NMP) is increasingly used for viability assessment of high-risk donor livers, whereas dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia-reperfusion injury. We aimed to resuscitate and test the viability of initially-discarded, high-risk donor livers using sequential DHOPE and NMP with two different oxygen carriers: an artificial hemoglobin-based oxygen carrier (HBOC) or red blood cells (RBC). In a prospective observational cohort study of 54 livers that underwent DHOPE-NMP, the first 18 procedures were performed with a HBOC-based perfusion solution and the subsequent 36 procedures were performed with an RBC-based perfusion solution for the NMP phase. All but one livers were derived from extended criteria donation after circulatory death donors, with a median donor risk index of 2.84 (IQR 2.52-3.11). After functional assessment during NMP, 34 livers (63% utilization), met the viability criteria and were transplanted. One-year graft and patient survival were 94% and 100%, respectively. Post-transplant cholangiopathy occurred in 1 patient (3%). There were no significant differences in utilization rate and post-transplant outcomes between the HBOC and RBC group. Ex situ machine perfusion using sequential DHOPE-NMP for resuscitation and viability assessment of high-risk donor livers results in excellent transplant outcomes, irrespective of the oxygen carrier used., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD., Methods: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE)., Discussion: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 ., (© 2022. The Author(s).)

Background: The specific effect of donation after circulatory death (DCD) liver grafts on fibrinolysis, blood loss, and transfusion requirements after graft reperfusion is not well known. The aim of this study was to determine whether transplantation of controlled DCD livers is associated with an elevated risk of hyperfibrinolysis, increased blood loss, and higher transfusion requirements upon graft reperfusion, compared with livers donated after brain death (DBD)., Methods: A retrospective single-center analysis of all adult recipients of primary liver transplantation between 2000 and 2019 was performed (total cohort n = 628). Propensity score matching was used to balance baseline characteristics for DCD and DBD liver recipients (propensity score matching cohort n = 218). Intraoperative and postoperative hemostatic variables between DCD and DBD liver recipients were subsequently compared. Additionally, in vitro plasma analyses were performed to compare the intraoperative fibrinolytic state upon reperfusion., Results: No significant differences in median (interquartile range) postreperfusion blood loss (1.2 L [0.5-2.2] versus 1.3 L [0.6-2.2]; P = 0.62), red blood cell transfusion (2 units [0-4] versus 1.1 units [0-3]; P = 0.21), or fresh frozen plasma transfusion requirements (0 unit [0-2.2] versus 0 unit [0-0.9]; P = 0.11) were seen in DCD compared with DBD recipients, respectively. Furthermore, plasma fibrinolytic potential was similar in both groups., Conclusions: Transplantation of controlled DCD liver grafts does not result in higher intraoperative blood loss or more transfusion requirements, compared with DBD liver transplantation. In accordance with this, no evidence for increased hyperfibrinolysis upon reperfusion in DCD compared with DBD liver grafts was found., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: End-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally., Methods and Analysis: This is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00-3:59 hour) or to the control arm (4:00-15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation., Ethics and Dissemination: The protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation., Trial Registration Number: NL8740., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients., Objective: The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis., Methods: The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort., Results: In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844])., Conclusions: A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated., (© 2021 The Authors. UEG Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited., Methods: In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications., Results: A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups., Conclusions: Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.)., (Copyright © 2021 Massachusetts Medical Society.)

With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes. From a national cohort of adult liver transplant recipients (1996-2016), all recipients transplanted with a liver from a DM donor (n = 69) were matched 1:2 with recipients of livers from non-DM donors (n = 138). The primary end-point included early post-transplant outcome, such as the incidence of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analysis was used to analyze the impact of donor DM on graft failure. PNF was observed in 5.8% of grafts from DM donors versus 2.9% of non-DM donor grafts (P = 0.31). Recipients of grafts derived from DM donors had a higher incidence of HAT (8.7% vs. 2.2%, P = 0.03) and decreased 90-day graft survival (88.4% [70.9-91.1] vs. 96.4% [89.6-97.8], P = 0.03) compared to recipients of grafts from non-DM donors. The adjusted hazard ratio for donor DM on graft survival was 2.21 (1.08-4.53, P = 0.03). In conclusion, donor DM is associated with diminished outcome early after liver transplantation. The increased incidence of HAT after transplantation of livers from DM donors requires further research., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar-ATPase (V-ATPase) assembly defects, various degrees of hepatic injury have been described, including end-stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in-depth analysis of the abnormal samples with quadruple time-of-flight mass spectrometry (QTOF-MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF-MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V-ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V-ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Donor hepatectomy time is associated with graft survival after liver transplantation. The aim of this study was to identify the impact of donor hepatectomy time on biliary injury during donation after circulatory death liver transplantation., Methods: First, bile duct biopsies of livers included in (pre)clinical machine perfusion research were analyzed. Secondly, of the same livers, bile samples were collected during normothermic machine perfusion. Lastly, a nationwide retrospective cohort study was performed including 273 adult patients undergoing donation after circulatory death liver transplantation between January 1, 2002 and January 1, 2017. Primary endpoint was development of non-anastomotic biliary strictures within 2 years of donation after circulatory death liver transplantation. Cox proportional-hazards regression analyses were used to assess the influence of hepatectomy time on the development of non-anastomotic biliary strictures., Results: Livers with severe histological bile duct injury had a higher median hepatectomy time (P = .03). During normothermic machine perfusion, livers with a hepatectomy time >50 minutes had lower biliary bicarbonate and bile pH levels. In the nationwide retrospective study, donor hepatectomy time was an independent risk factor for non-anastomotic biliary strictures after donation after circulatory death liver transplantation (Hazard Ratio 1.18 per 10 minutes increase, 95% Confidence Interval 1.06-1.30, P value = .002)., Conclusion: Donor hepatectomy time negatively influences histological bile duct injury before normothermic machine perfusion and bile composition during normothermic machine perfusion. Additionally, hepatectomy time is a significant independent risk factor for the development of non-anastomotic biliary strictures after donation after circulatory death liver transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Due to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD), especially donation after circulatory death (DCD), for reLT are lacking. We aimed to assess the outcome of patients undergoing reLT using a DCD graft in the Netherlands between 2001 and July 2018. Propensity score matching was used to match each DCD-reLT with three DBD-reLT cases. Primary outcomes were patient and graft survival. Secondary outcome was the incidence of biliary complications, especially nonanastomotic strictures (NAS). 21 DCD-reLT were compared with 63 matched DBD-reLTs. Donors in the DCD-reLT group had a significantly lower BMI (22.4 vs. 24.7 kg/m 2 , P-value = 0.02). Comparison of recipient demographics and ischemia times yielded no significant differences. Patient and graft survival rates were comparable between the two groups. However, the occurrence of nonanastomotic strictures after DCD-reLT was significantly higher (38.1% vs. 12.7%, P-value = 0.02). ReLT with DCD grafts does not result in inferior patient and graft survival compared with DBD grafts in selected patients. Therefore, DCD liver grafts should not routinely be declined for patients awaiting reLT., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Short-term survival after orthotopic liver transplantation (OLT) has improved over the past decades, but long-term survival remains impaired. The effects of obesity on long-term survival after OLT are controversial. Because pre-transplant body mass index (BMI) can be confounded by ascites, we hypothesized that post-transplant BMI at 1 year could predict long-term survival., Methods: A post-hoc analysis was performed of an observational cohort study consisting of adult recipients of a first OLT between 1993 and 2010. Baseline BMI was measured at 1-year post-transplantation to represent a stable condition. Recipients were stratified into normal weight (BMI < 25 kg/m 2 ), overweight (25 ≤ BMI ≤ 30 kg/m 2 ), and obese (BMI > 30 kg/m 2 ). Kaplan-Meier survival analyses were performed with log-rank testing, followed by multivariable Cox proportional hazards regression analysis., Results: Out of 370 included recipients, 184 had normal weight, 136 were overweight, and 50 were obese at 1-year post-transplantation. After median follow-up for 12.3 years, 107 recipients had died, of whom 46 (25%) had normal weight, 39 (29%) were overweight, and 22 (44%) were obese (log-rank P = 0.020). Obese recipients had a significantly increased mortality risk compared to normal weight recipients (HR 2.00, 95% CI 1.08-3.68, P = 0.027). BMI was inversely associated with 15 years patient survival (HR 1.08, 95% CI 1.03-1.14, P = 0.001 per kg/m 2 ), independent of age, gender, muscle mass, transplant characteristics, cardiovascular risk factors, kidney- and liver function., Conclusion: Obesity at 1-year post-transplantation conveys a 2-fold increased mortality risk, which may offer potential for interventional strategies (i.e. dietary advice, lifestyle modification, or bariatric surgery) to improve long-term survival after OLT., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)