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Background & Aims: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes., Methods: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared., Results: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22)., Conclusion: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup., Impacts and Implications: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Utility, a major principle for allocation in the context of transplantation, is questioned in patients with acute-on chronic liver failure grade 3 (ACLF-3) who undergo liver transplantation (LT). We aimed to explore long-term outcomes of patients included in a three-centre retrospective French study published in 2017., Method: All patients with ACLF-3 (n = 73), as well as their transplanted matched controls with ACLF-2 (n = 145), 1 (n = 119) and no ACLF (n = 292), who participated in the Princeps study published in 2017 were included. We explored 5- and 10-year patient and graft survival rates, causes of death and their predictive factors., Results: Median follow-up of patients with ACLF-3 was 7.5 years. At LT, median MELD was 40. In patients with ACLF-3, 2, 1 and no ACLF, 5-year patient survival rates were 72.6% vs. 69.7% vs. 76.4% vs. 77.0%, respectively (p = 0.31). Ten-year patient survival for ACLF-3 was 56.8% and was not different to other groups (p = 0.37). Leading causes of death in patients with ACLF-3 were infections (33.3%) and cardiovascular events (23.3%). After exclusion of early death, UCLA futility risk score, age-adjusted Charlson comorbidity index and CLIF-C ACLF score were independently associated with 10-year patient survival. Long-term graft survival rates were not different across the groups. Clinical frailty scale and WHO performance status improved over time in patients alive after 5 years., Conclusion: 5- and 10-year patient and graft survival rates were not different in patients with ACLF-3 compared to matched controls. 5-year patient survival is higher than the 50%-70% threshold defining the utility of a liver graft. Efforts should focus on candidate selection based on comorbidities, as well as the prevention of infection and cardiovascular events., Impact and Implications: While short-term outcomes following liver transplantation in the most severely ill patients with cirrhosis (acute-on-chronic liver failure grade 3 [ACLF-3]) are known, long-term data are limited, raising questions about the utility of graft allocation in the context of scarce medical resources. This study provides a favourable long-term update, confirming no differences in 5- and 10-year patient and graft survival following liver transplantation in patients with ACLF-3 compared to matched patients with ACLF-2, ACLF-1, and no-ACLF. The study highlights the risk of dying from infection and cardiovascular causes in the long-term and identifies scores including comorbidity evaluation, such as the age-adjusted Charlson comorbidity index, as independently associated with long-term survival. Therefore, physicians should consider the cumulative burden of comorbidities when deciding whether to transplant these patients. Additionally, after transplantation, the study encourages mitigating infectious risk with tailored immunosuppressive regimens and tightly managing cardiovascular risk over time., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The recent discovery of Hepatitis D (HDV)-like viruses across a wide range of taxa led to the establishment of the Kolmioviridae family. Recent studies suggest that kolmiovirids can be satellites of viruses other than Hepatitis B virus (HBV), challenging the strict HBV/HDV-association dogma. Studying whether kolmiovirids are able to replicate in any animal cell they enter is essential to assess their zoonotic potential. Here, we compared replication of three kolmiovirids: HDV, rodent (RDeV) and snake (SDeV) deltavirus in vitro and in vivo. We show that SDeV has the narrowest and RDeV the broadest host cell range. High resolution imaging of cells persistently replicating these viruses revealed nuclear viral hubs with a peculiar RNA-protein organization. Finally, in vivo hydrodynamic delivery of viral replicons showed that both HDV and RDeV, but not SDeV, efficiently replicate in mouse liver, forming massive nuclear viral hubs. Our comparative analysis lays the foundation for the discovery of specific host factors controlling Kolmioviridae host-shifting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khalfi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone's metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone's oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver., (© 2024. The Author(s).)

Hydrodynamic tail vein injection (HTVi), also called hydrodynamic gene transfer (HGT), is attracting increasing interest for modeling hepatic carcinogenesis. This highly versatile approach reproducibly provides efficient in vivo transfection of hepatocytes with naked DNA. Here, we give an in-depth description of the injection procedure, which is key for the success of the method. HTVi requires the injection of a large volume of a solution containing plasmids into the tail vein of the mouse. The transient right heart overload created by the injection forces the blood to flow back into the hepatic veins, enlarging the endothelial fenestrae and permeabilizing a fraction of hepatocytes for a few seconds. This results in the uptake of plasmids by the permeabilized hepatocytes, giving rise to their in vivo transfection. Including the Sleeping Beauty transposon system among the injected plasmids leads to the stable transfection of a subset of hepatocytes. HTVi is a powerful technique which enables numerous applications in liver cancer biology, such as a study of oncogene cooperation, of tumor heterogeneity, and interaction with the tumor microenvironment., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Stereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT., Materials and Methods: We prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions., Results: Between October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed., Conclusion: MRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background & Aims: Liver transplantation (LT) is a last resort treatment for patients at high risk of mortality from end-stage liver disease. Over the past years, alcohol-associated liver disease has become the most frequent indication for LT in the world. The outcomes of LT for alcohol-associated liver disease are good, but return to alcohol use is detrimental for medium-term survival because of cancer development, cardiovascular events, and recurrent alcohol-associated cirrhosis. Several strategies have been developed to prevent return to alcohol use during the pre- or post-LT period, but there are no specific recommendations. Therefore, the main objective of this study was to investigate if the integration of an addiction team in a LT unit affected the rate of severe alcohol relapse after LT. The secondary objectives were to assess the effects of addiction follow up on cardiovascular events, cancer, and overall survival., Methods: This study was a retrospective comparison between centres with or without addiction monitoring., Results: The study included 611 patients of which 79.4% were male with a mean age of 55.4 years at the time of LT, 190 were managed by an integrated addiction team. The overall alcohol relapse rate was 28.9% and the rate of severe relapse was 13.0%. Patients with addiction follow-up had significantly less frequent severe alcohol relapse than those in the control group ( p  = 0.0218). Addiction follow up (odds ratio = 0.19; p  = 0.001) and age at LT (odds ratio = 1.23; p  = 0.02) remained significantly associated with post-LT cardiovascular events., Conclusions: Our study confirms the benefits of integrating an addiction team to reduce return to alcohol use after LT., Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT04964687)., Impact and Implications: The main indication for liver transplantation is alcohol-associated cirrhosis. There are currently no specific recommendations on the addiction monitoring of transplant candidates, although severe return to alcohol use after liver transplantation has a negative impact on long-term survival of patients. In this study, we explored the impact of a systematic addiction intervention on the return to alcohol use rates. In our transplantation centre, we demonstrated the interest of an addiction follow up to limit the severe alcohol relapses rate. This information should be further investigated in prospective studies to validate these data., Competing Interests: The authors declare they have no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Surgical resection is the optimal treatment for HCC, despite a high risk of recurrence. Few data are available on patient’s survival after resection. This is a retrospective study of tumor recurrence occurring after hepatectomy for HCC from 2000 to 2016. Univariate and multivariate analyses were performed to identify prognostic factors of survival after recurrence (SAR). Among 387 patients, 226 recurred (58.4%) with a median SAR of 26 months. Curative treatments (liver transplantation, repeat hepatectomy, thermal ablation) were performed for 44.7% of patients. Independent prognostic factors for SAR were micro-vascular invasion on the primary surgical specimen, size of the initial tumor >5 cm, preoperative AFP, albumin and platelet levels, male gender, number, size and localization of tumors at recurrence, time to recurrence, Child−Pugh score and treatment at recurrence. In subgroup analysis, early recurrence (46%) was associated with a decrease in SAR, by contrast with late recurrence. However, the overall survival (OS) of patients with early recurrence and curative treatment did not significantly differ from that of non-recurring patients. For late recurrence, OS did not significantly differ from that of non-recurring patients, regardless of the proposed treatment. Aggressive and repeat treatments are therefore key to improve prognosis of patients with HCC.

Background US tools to quantify liver fat content have recently been made clinically available by different vendors, but comparative data on their accuracy are lacking. Purpose To compare the diagnostic performances of the attenuation parameters of US machines from three different manufacturers (vendors 1, 2, and 3) in participants who underwent liver fat quantification with the MRI-derived proton density fat fraction (PDFF). Materials and Methods From July 2020 to June 2021, consecutive participants with chronic liver disease were enrolled in this prospective single-center study and underwent MRI PDFF quantification (reference standard) and US on the same day. US was performed with two different machines from among three vendors assessed. Areas under the receiver operating characteristic curve (AUCs) for the staging of liver steatosis (MRI PDFF: ≥5.5% for grade ≥S1 and ≥15.5% for grade ≥S2) were calculated in test and validation samples and then compared between vendors in the study sample. Results A total of 534 participants (mean age, 60 years ± 13 [SD]; 320 men) were evaluated. Failure of measurements occurred in less than 1% of participants for all vendors. Correlation coefficients with the MRI PDFF were 0.71, 0.73, and 0.54 for the attenuation coefficients of vendors 1, 2, and 3, respectively. In the test sample, AUCs for diagnosis of steatosis grade S1 and higher and grade S2 and higher were 0.89 and 0.93 for vendor 1 attenuation, 0.88 and 0.92 for vendor 2 attenuation, and 0.79 and 0.79 for vendor 3 attenuation, respectively. In the validation sample, a threshold value of 0.65 for vendor 1 and 0.66 for vendor 2 yielded sensitivity of 77% and 84% and specificity of 78% and 85%, respectively, for diagnosis of grade S1 and higher. Vendor 2 attenuation had greater AUCs than vendor 3 attenuation ( P = .001 and P = .003) for diagnosis of grade S1 and higher and grade S2 and higher, respectively, and vender 2 had greater AUCs for attenuation than vendor 1 for diagnosis of grade S2 and higher ( P = .04). For all vendors, attenuation was not associated with liver stiffness (correlation coefficients <0.05). Conclusion To stage liver steatosis, attenuation coefficient accuracy varied among US devices across vendors when using MRI proton density fat fraction quantification as the reference standard, with some demonstrating excellent diagnostic performance and similar cutoff values. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Dubinsky in this issue.

Percutaneous thermal ablation (PTA), resection, and liver transplantation are the standard curative options for hepatocellular carcinoma (HCC). Liver transplantation yields the best long-term outcomes but is limited by graft shortage. Thus, patients with ≤3-cm HCC are primarily treated by PTA even though recurrence is frequent and may occur outside transplant criteria. Data on non-transplantable recurrence (NTR) following PTA are lacking, however. We therefore investigated the incidence and predictors of NTR among 213 potentially transplantable patients (cirrhosis, 93%; Child-Pugh A, 98.6%; alcohol-related disease, 62%) with ≤3-cm HCC(s) treated by PTA, to stratify them according to their NTR risk and to improve treatment allocation. During follow-up (median: 41.2 months), NTR occurred in 18.3% (alpha-fetoprotein [AFP] model) and 23% (Milan) patients. NTR prediction with competing-risk analysis and internal validation revealed AFP > 100 ng/ml (subdistribution hazard ratio: 7.28; p < 0.001) and prior HCC (subdistribution hazard ratio: 3.77; p = 0.002) as independent predictors (Harrell's C: 0.76). Based on this model using the AFP score (equally predictive within Milan criteria), patients were stratified into three NTR risk categories: HCC-naïve with AFP < 100 ng/ml (low risk, n = 108 of 213), non-HCC naïve with AFP < 100 ng/ml (intermediate risk, n = 92 of 213), AFP ≥ 100 ng/ml (high risk, n = 13 of 213), among whom 9.3% (3.7% [Milan]), 22.8% (25% [Milan]), and 61.5% (38/5% [Milan]) presented NTR (p < 0.001). Median recurrence-free survival was 4.6, 14.5, and 43.4 months, respectively, in high-risk, intermediate-risk, and low-risk categories (p < 0.001). Median overall survival, which was 19.1 months in high-risk patients, was not reached otherwise (p < 0.001). Conclusion: Overall, PTA of ≤3-cm HCC incurs a low NTR risk. Simple and noninvasive predictors (HCC naivety, AFP) accurately stratified patients' risk of NTR, and should help to improve treatment allocation. Patients with AFP ≥ 100 ng/ml have a high risk of NTR, poor recurrence-free survival, and overall survival. Further studies evaluating preemptive transplantation or adjuvant/neoadjuvant strategies are highly needed in this small patient subset., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I 2 index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival., (© 2022 American Association for the Study of Liver Diseases.)

Background and Aims: After 2 doses, the efficacy of anti-SARS-CoV-2 vaccination seems to be lower in solid organ transplant recipients than in the immunocompetent population. The objective of this study was to determine the humoral response rate after vaccination, including with a booster dose, and to identify risk factors for non-responsiveness in liver transplant recipients., Methods: We included all patients seen in consultation in two French liver transplant centres between January 1, 2021, and March 15, 2021., Results: 598 liver transplant recipients were enrolled and 327 were included for analysis. Sixteen patients received one dose, 63 patients two doses and 248 patients three doses. Anti-SARS-Cov-2 antibodies were detected in 242 out of 327 (74.0%) liver transplant patients after vaccination. Considering an optimal serologic response defined as an antibody titre >260 BAU/ml, 172 patients (52.6%) were responders. Mycophenolate mofetil (MMF) treatment was an independent risk factor for a failure to develop anti-SARS-CoV-2 antibodies after vaccination (OR 0.458; 95%CI 0.258-0.813; p = .008). Conversely, male gender (OR 2.247, 95%CI 1.194-4.227; p = .012) and receiving an mRNA vaccine (vs a non-mRNA vaccine) (OR 4.107, 95%CI 1.145-14.731; p = .030) were independent predictive factors for developing an optimal humoral response after vaccination. None of the patients who received the vaccine experienced any serious adverse events., Conclusions: Even after a third booster dose, response rate to vaccination is decreased in liver transplant recipients. MMF appears to be a major determinant of seroconversion and optimal response to vaccination in these patients., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Fibroblast growth factor 19 (FGF19) is a hormone with pleiotropic metabolic functions, leading to ongoing development of analogues for treatment of metabolic disorders. On the other hand, FGF19 is overexpressed in a sub-group of hepatocellular carcinoma (HCC) patients and has oncogenic properties. It is therefore crucial to precisely define FGF19 effects, notably in the context of chronic exposure to elevated concentrations of the hormone. Here, we used hydrodynamic gene transfer to generate a transgenic mouse model with long-term FGF19 hepatic overexpression. We describe a novel effect of FGF19, namely the stimulation of water intake. This phenotype, lasting at least over a 6-month period, depends on signaling in the central nervous system and is independent of FGF21, although it mimics some of its features. We further show that HCC patients with high levels of circulating FGF19 have a reduced natremia, indicating dipsogenic features. The present study provides evidence of a new activity of FGF19, which could be clinically relevant in the context of FGF19 overexpressing cancers and in the course of treatment of metabolic disorders by FGF19 analogues., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Various population pharmacokinetic models have been developed to describe the pharmacokinetics of tacrolimus in adult liver transplantation. However, their extrapolated predictive performance remains unclear in clinical practice. The purpose of this study was to predict concentrations using a selected literature model and to improve these predictions by tweaking the model with a subset of the target population., Methods: A literature review was conducted to select an adequate population pharmacokinetic model (L). Pharmacokinetic data from therapeutic drug monitoring of tacrolimus in liver-transplanted adults were retrospectively collected. A subset of these data (70%) was exploited to tweak the L-model using the $PRIOR subroutine of the NONMEM software, with 2 strategies to weight the prior information: full informative (F) and optimized (O). An external evaluation was performed on the remaining data; bias and imprecision were evaluated for predictions a priori and Bayesian forecasting., Results: Seventy-nine patients (851 concentrations) were enrolled in the study. The predictive performance of L-model was insufficient for a priori predictions, whereas it was acceptable with Bayesian forecasting, from the third prediction (ie, with ≥2 previously observed concentrations), corresponding to 1 week after transplantation. Overall, the tweaked models showed a better predictive ability than the L-model. The bias of a priori predictions was -41% with the literature model versus -28.5% and -8.73% with tweaked F and O models, respectively. The imprecision was 45.4% with the literature model versus 38.0% and 39.2% with tweaked F and O models, respectively. For Bayesian predictions, whatever the forecasting state, the tweaked models tend to obtain better results., Conclusions: A pharmacokinetic model can be used, and to improve the predictive performance, tweaking the literature model with the $PRIOR approach allows to obtain better predictions., Competing Interests: J. Ursic-Bedoya has received travel grants from Astellas outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Alcohol abstinence before liver transplantation (LT) for alcohol-associated liver disease (ALD) is required for every candidate. Some listed patients might relapse, resulting in LT for patients nonabstinent during the pretransplant period. Long-term survival outcomes of these patients have never been studied. We sought to determine whether alcohol consumption on the day of the LT influenced long-term survival after LT. We conducted a retrospective case-control study among French LT centers. Cases were defined as recipients between January 1995 and December 2007 having positive blood and/or urine alcohol levels the day of LT. Each case was paired with 2 controls corresponding to patients transplanted for ALD during the same trimester. Patients were classified into 3 categories per alcohol consumption: abstainers, occasional or transitory excessive consumers, or patients with a sustained excessive consumption (daily consumption >20-30 g/day). During the study period, 3052 LTs for ALD were conducted in France. We identified 42 cases paired with 84 controls. Median blood alcohol level was 0.4 g/L (range 0.1-4.1 g/L) and median urine alcohol level was 0.2 g/L (range 0.1-2.0 g/L). Median follow-up period until death or censoring was 12.9 years (CI 95% = [12.3; 13.6]). Long-term survival was not different between the groups. Relapse to any alcohol consumption rate was higher in the case group (59.5%) than in the control group (38.1%, odds ratio 2.44; CI 95% = [1.13; 5.27]), but sustained excessive consumption was not significantly different between the groups (33.3% versus 29.8% in case and control groups respectively, χ 2  = 0.68). Rates of recurrent cirrhosis and cirrhosis-related deaths were more frequent in the case group. Liver transplantation for nonabstinent patients during the immediate pretransplant period does not result in impaired long-term survival despite higher relapse and recurrent cirrhosis rates., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Percutaneous thermal ablation is a validated treatment option for small hepatocellular carcinoma (HCC). Steatotic HCC can be reliably detected by magnetic resonance imaging. To determine the clinical relevance of this radiological variant, we included 235 patients (cirrhosis in 92.3%, classified Child-Pugh A in 97%) from a prospective database on percutaneous thermal ablation for <3 cm HCC. Among these patients, 52 (22.1%) had at least one steatotic HCC nodule. Nonalcoholic steatohepatitis was more frequent in patients with than without steatotic HCC ( P  = 0.057), whereas body mass index, diabetes mellitus, liver steatosis, and liver fat content did not differ between groups. Liver disease was less advanced in patients with than without steatotic HCC: lower total bilirubin ( - 2.1 µmol/L; P  = 0.035), higher albumin (+0.8 g/L; P  = 0.035), and lower Model for End-Stage Liver Disease score (-0.8; P  = 0.014). Tumor phenotype was less aggressive in patients with steatotic HCC: lower alpha-fetoprotein (AFP) concentration ( P  = 0.019), less frequent AFP > 100 ng/mL ( P  = 0.045), and multifocality ( P  = 0.015). During the follow-up (median: 28.3 months), overall mortality (3.8% vs. 23.5%; P  = 0.001) and HCC-specific mortality (0.0% vs. 14.2%; P  = 0.002) rates were lower in patients with steatotic HCC. Early (<2 years) recurrence was also less frequent (32.7% vs. 49.2%; P  = 0.041). The mean time to intrahepatic distant recurrence (16.4 vs. 9 months, P  = 0.006) and the median time to recurrence and recurrence-free survival (32.4 vs. 18.6 months, P  = 0.024 and 30.4 vs. 16.4 months, P  = 0.018) were longer in patients with steatotic versus nonsteatotic HCC. The 3-year overall survival was 94.4% and 70.9% in steatotic and nonsteatotic HCC ( P  = 0.008). In multivariate analysis, steatotic HCC (hazard ratio = 0.12; P  = 0.039) and AFP (HR=1.002; P  < 0.001) independently predicted overall survival. Conclusion: Small steatotic HCC detected by magnetic resonance imaging is associated with a less aggressive tumor phenotype. In patients with such radiological variant, percutaneous thermal ablation results in improved outcome., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload., Methods: Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy., Results: The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy., Conclusions: BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions., Lay Summary: Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy., Competing Interests: The authors declare no conflicts of interest that pertain to this work., (© 2020 The Authors.)

During liver repair after injury, bile secretion has to be tightly modulated in order to preserve liver parenchyma from bile acid (BA)-induced injury. The mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides their historical role in lipid digestion, bile acids (BA) and their receptors constitute a signalling network with multiple impacts on liver repair, both stimulating regeneration and protecting the liver from BA overload. BA signal through nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors to elicit a wide array of biological responses. While a great number of studies have been dedicated to the hepato-protective impact of FXR signalling, TGR5 is by far less explored in this context. Because the liver has to face massive and potentially harmful BA overload after partial ablation or destruction, BA-induced protective responses crucially contribute to spare liver repair capacities. Based on the available literature, the TGR5 BA receptor protects the remnant liver and maintains biliary homeostasis, mainly through the control of inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity and sinusoidal blood flow. Mouse experimental models of liver injury reveal that in the lack of TGR5, excessive inflammation, leaky biliary epithelium and hydrophobic BA overload result in parenchymal insult and compromise optimal restoration of a functional liver mass. Translational perspectives are thus opened to target TGR5 with the aim of protecting the liver in the context of injury and BA overload., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) score is an HLA epitope matching algorithm. PIRCHE algorithm estimates the level of presence of T-cell epitopes in mismatched HLA. The PIRCHE-II numbers associate with de novo donor-specific antibody (dnDSA) formation following liver transplantation and kidney allograft survival following renal transplantation. The aim of our study was to assess the PIRCHE-II score in calcineurin inhibitor (CNI)-free maintenance immunosuppression recipients. This was a retrospective study of forty-one liver transplant recipients on CNI-free immunosuppression and with available liver allograft biopsies. Donors and recipients were HLA typed. The HLA-derived mismatched peptide epitopes that could be presented by the recipient's HLA-DRB1 molecules were calculated using PIRCHE-II algorithm. The associations between PIRCHE-II scores and graft immune-mediated events were assessed using receiver operating characteristics curves and subsequent univariate and multivariate analyses. CNI-free patients with cellular rejection, humoral rejection, or severe portal inflammation had higher mean PIRCHE-II scores compared to patients with normal liver allografts. PIRCHE-II score and donor age were independent risk factors for liver graft survival in CNI-free patients (HR: 8.0, 95% CI: 1.3-49, p = .02; and HR: 0.88, 95% CI: 0.00-0.96, p = .007, respectively). PIRCHE-II scores could be predictive of liver allograft survival in CNI-free patients following liver transplantation. Larger studies are needed to confirm these results., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). Severe alcohol relapse can rapidly lead to recurrent alcohol-related cirrhosis (RAC) for the graft. The aim of this study was to describe the natural history of RAC and the overall survival after LT and after an RAC diagnosis. From 1992 to 2012, 812 patients underwent primary LT for ALD in 5 French transplant centers. All patients with severe alcohol relapse and an RAC diagnosis on the graft were included. The diagnosis of cirrhosis was based on the analysis of liver biopsy or on the association of clinical, biological, radiological, and/or endoscopic features of cirrhosis. RAC was diagnosed in 57/162 patients (35.2%) with severe alcohol relapse, and 31 (54.4%) of those patients had at least 1 episode of liver decompensation. The main types of decompensation were ascites (70.9%), jaundice (58.0%), and hepatic encephalopathy (9.6%). The cumulative probability of decompensation was 23.8% at 5 years, 50.1% at 10 years, and 69.9% at 15 years after LT. During the follow-up, 36 (63.2%) patients died, the main cause of death being liver failure (61.1%). After diagnosis of cirrhosis, the survival rate was 66.3% at 1 year, 37.8% at 5 years, and 20.6% at 10 years. In conclusion, RAC is associated with a high risk of liver decompensation and a poor prognosis. Prevention of severe alcohol relapse after LT is a major goal to improve patient survival., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Objective: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability., Design: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied., Results: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice., Conclusion: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Up to 50% of liver transplantation (LT) recipients with known or clandestine alcohol-use disorder (AUD) before surgery return to alcohol use after LT. However, only severe alcohol relapse, which varies in frequency from 11% to 26% of patients, has an impact on longterm survival and significantly decreases survival rates after 10 years. Therefore, it is crucial to identify patients with the highest risk of severe relapse in order to arrange specific, standardized monitoring by an addiction team before and after LT. The aims of this study were to describe the effects of combined management of AUD on the rate of severe alcohol relapse and to determine the risk factors before LT that predict severe relapse. Patients transplanted between January 2008 and December 2014 who had met with the LT team's addiction specialist were included in the study. Patients who exhibited alcohol-related relapse risk factors received specific addiction follow-up. A total of 235 patients were enrolled in the study. Most of them were men (79%), and the mean age at the time of the LT was 55.7 years. Severe relapse occurred in only 9% of the transplant recipients. Alcohol-related factors of severe relapse were a pretransplant abstinence of 6 months and family, legal, or professional consequences of alcohol consumption, whereas the nonalcohol-related factors were being single and being eligible for a disability pension. In conclusion, the integration of an addiction team in a LT center may be beneficial. The addiction specialist can identify patients at risk of severe relapse in the pretransplantation period and hence arrange for specific follow-up., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Purpose: To identify predictive factors of tumor response, progression-free survival (PFS), overall survival (OS), and toxicity using three-dimensional (3D) voxel-based dosimetry in patients with intermediate and advanced stage hepatocellular carcinoma (HCC) treated by yttrium-90 ( 90 Y) resin microspheres radioembolization (RE)., Materials and Methods: From February 2012 to December 2015, 45 90 Y resin microspheres RE procedures were performed for HCC (Barcelona Clinic Liver Cancer stage B/C; n = 15/30). Area under the dose-volume histograms (AUDVHs) were calculated from 3D voxel-based dosimetry to measure 90 Y dose deposition. Factors associated with tumor control (ie, complete/partial response or stable disease on Modified Response Evaluation Criteria in Solid Tumors) at 6 months were investigated. PFS and OS analyses were performed (Kaplan-Meier). Toxicity was assessed by occurrence of radioembolization-induced liver disease (REILD)., Results: Tumor control rate was 40.5% (17/42). Complete tumor targeting (odds ratio = 36.97; 95% confidence interval, 1.83-747; P < .001) and AUDVH tumor (odds ratio = 1.027; 95% confidence interval, 1.002-1.071; P = .033) independently predicted tumor control. AUDVH tumor ≥ 61 Gy predicted tumor control with 76.5% sensitivity and 75% specificity. PFS and OS in patients with incomplete tumor targeting were significantly shorter than in patients with complete tumor targeting (median PFS, 2.7 months [range, 0.8-4.6 months] vs 7.9 months [range, 2.1-39.5 months], P < .001; median OS, 4.5 months [range, 1.4-23 months] vs 19.2 months [range, 2.1-46.9 months], P < .001). Patients with incomplete tumor targeting and AUDVH tumor < 61 Gy, incomplete tumor targeting and AUDVH tumor > 61 Gy, complete tumor targeting and AUDVH tumor < 61 Gy, and AUDVH tumor > 61 Gy had median PFS of 2.7, 1.8, 6.3, and 12.1 months (P < .001). REILD (n = 4; 9.5%) was associated with higher dose delivered to normal liver (P = .04)., Conclusions: Complete tumor targeting and 90 Y dose to tumor are independent factors associated with tumor control and clinical outcomes., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Nonmelanoma skin cancers (NMSCs) are the most frequent cancers in solid organ transplant recipients, with a high rate of subsequent tumors., Objectives: To describe subsequent NMSCs in a large cohort of liver transplant recipients (LTRs) with long follow-up and analyze the factors influencing it, including immunosuppressive regimen., Methods: A total of 96 LTRs (76 male) with a personal post-transplant history of squamous cell carcinoma, basal cell carcinoma or Bowen's disease were included, with a median follow-up of 12.4 years (range, 1.5-27.8) after liver transplantation., Results: The median follow-up after first NMSC was 6.4 years (range, 0.17-22.1). In all, 52 patients (53.1%) developed 141 subsequent NMSCs with a basal cell carcinoma-to-squamous cell carcinoma ratio of 1.8:1. The actuarial risk for development of a second NMSC was 13.7% at 1 year, 28.4% at 2 years, 49.4% at 5 years, 65.7% at 10 years, and 88.4% at 15 years. Multivariate analysis found that skin phototype I or II (vs III or IV) was a significant risk factor for development of a second NMSC (hazard ratio, 2.556; 95% confidence interval, 1.45-4.48; P = .001), whereas withdrawal of calcineurin inhibitors was significantly protective (hazard ratio, 0.358; 95% confidence interval, 0.142-0.902; P = .029)., Limitations: Retrospective analysis., Conclusions: Subsequent NMSCs are very frequent in LTRs, and conversion from a calcineurin inhibitor-based immunosuppressive regimen to a mammalian target of rapamycin inhibitor/antimetabolite-based immunosuppressive regimen can reduce subsequent NMSCs., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although very rare, pantoprazole can result in acute hepatitis. It has yet to be reported, however, that it can also cause chronic autoimmune hepatitis., Aim, Method and Results: We report the case of a patient in whom pantoprazole administration for 2 months was followed by acute liver injury with severe jaundice and features of autoimmunity. A liver biopsy revealed acute hepatocellular lesions associated with cholestasis, acute cholangitis and polymorphous inflammatory infiltration suggestive of drug-induced liver injury. The jaundice disappeared following discontinuation of the pantoprazole. There was, however, chronic autoimmune liver injury, with the occurrence of extensive liver fibrosis within a few months. This led to the administration of immunosuppressive agents, which led to progressive and complete recovery associated with the disappearance of autoantibodies., Conclusion: This observation further supports the notion that pantoprazole can induce acute hepatocellular hepatitis, and it strongly suggests that it may trigger acute cholangitis and autoimmune liver injury. This case also helps document that some drugs can induce chronic autoimmune hepatitis that can resolve with immunosuppressive treatment., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The hepatic vein access during transjugular intrahepatic portosystemic shunt (TIPS) can be challenging in liver transplant recipient patients, especially when piggyback anastomosis was performed. We described a modified technique and reviewed the clinical outcomes of TIPS in transplanted patients., Materials and Methods: From 2015 to 2016, 8 patients with history of liver transplantation using a three-hepatic vein piggyback technique for venous anastomosis underwent a TIPS in our institution. Indications were refractory ascites (n = 7) or variceal bleeding (n = 1). When the hepatic vein access failed via the standard jugular route, a pull-through technique was used: After puncturing the right hepatic vein under ultrasound guidance, a guidewire and a vascular sheath were advanced, then the guidewire was snared in the inferior vena cava and retrieved though the jugular access, and the hepatic vein was catheterized along the guidewire. The safety and technical success rates of this technique and the clinical outcomes of the study population were retrospectively assessed., Results: Seven of 8 patients (87.5%) required the pull-through technique to access a hepatic vein. No complications of the percutaneous access of the hepatic vein were found at the one-day and one-month ultrasound Doppler examinations. Among 7 patients who had refractory ascites, 3 had complete resolution of ascites (43%), and one had moderate improvement. One patient with refractory infected ascites on severe graft failure and one with massive bleeding died soon after the procedure., Conclusion: A pull-through technique following percutaneous puncture of a hepatic vein is a safe technique for performing a TIPS in liver transplant recipients with piggyback anastomosis complicated by acute hepatic vein angulation.

Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) is a common event that has been extensively studied. In contrast, alcohol consumption has usually been neglected in patients transplanted for other liver diseases. First off, patients can be mislabeled as 'non-ALD' when they suffer from another chronic liver disease. Then, alcohol consumption is not systematically tracked after LT in recipients having a primary indication other than ALD, although there are increasing data incriminating alcohol as responsible for graft damage and impaired survival. This review discusses the potential consequences of alcohol after liver transplantation, focusing on patients transplanted for non-alcoholic liver disease, as well as the legitimate role of an addiction specialist, before and after LT., Short Summary: Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) is a common event that has been extensively studied. In contrast, alcohol consumption has usually been neglected in patients transplanted for other liver diseases. There are increasing data showing that alcohol consumption and its consequences should be tracked in every transplant candidate and recipient.

Background & Aims: Liver transplantation (LT) for the most severely ill patients with cirrhosis, with multiple organ dysfunction (accurately assessed by the acute-on-chronic liver failure [ACLF] classification) remains controversial. We aimed to report the results of LT in patients with ACLF grade 3 and to compare these patients to non-transplanted patients with cirrhosis and multiple organ dysfunction as well as to patients transplanted with lower ACLF grade., Methods: All patients with ACLF-3 transplanted in three liver intensive care units (ICUs) were retrospectively included. Each patient with ACLF-3 was matched to a) non-transplanted patients hospitalized in the ICU with multiple organ dysfunction, or b) control patients transplanted with each of the lower ACLF grades (three groups)., Results: Seventy-three patients were included. These severely ill patients were transplanted following management to stabilize their condition with a median of nine days after admission (progression of mean organ failure from 4.03 to 3.67, p=0.009). One-year survival of transplanted patients with ACLF-3 was higher than that of non-transplanted controls: 83.9 vs. 7.9%, p<0.0001. This high survival rate was not different from that of matched control patients with no ACLF (90%), ACLF-1 (82.3%) or ACLF-2 (86.2%). However, a higher rate of complications was observed (100 vs. 51.2 vs. 76.5 vs. 74.3%, respectively), with a longer hospital stay. The notion of a "transplantation window" is discussed., Conclusions: LT strongly influences the survival of patients with cirrhosis and ACLF-3 with a 1-year survival similar to that of patients with a lower grade of ACLF. A rapid decision-making process is needed because of the short "transplantation window" suggesting that patients with ACLF-3 should be rapidly referred to a specific liver ICU. Lay summary: Liver transplantation improves survival of patients with very severe cirrhosis. These patients must be carefully monitored and managed in a specialized unit. The decision to transplant a patient must be quick to avoid a high risk of mortality., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Liver transplantation (LT) is the gold standard treatment for end-stage liver disease. Whatever the primary indication of LT, substance abuse after surgery may decrease survival rates and quality of life. Prevalence of severe alcohol relapse is between 11 and 26%, and reduces life expectancy regardless of the primary indication of LT. Many patients on waiting lists for LT are smokers and this is a major risk factor for both malignant tumors and cardiovascular events post-surgery. The aim of this review is to describe psychoactive substance consumption after LT, and to assess the impact on liver transplant recipients. This review describes data about alcohol and illicit drug use by transplant recipients and suggests guidelines for behavior management after surgery. The presence of an addiction specialist in a LT team seems to be very important., Competing Interests: Conflict-of-interest statement: The authors declare there is no conflict of interest.

Tissue repair is orchestrated by a finely tuned interplay between processes of regeneration, inflammation and cell protection, allowing organisms to restore their integrity after partial loss of cells or organs. An important, although largely unexplored feature is that after injury and during liver repair, liver functions have to be maintained to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely modulated in order to preserve liver parenchyma from bile-induced injury. However, mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides cytokines and growth factors, bile acids (BA) and their receptors constitute an insufficiently explored signaling network during liver regeneration and repair. BA signal through both nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors which distributions are large in the organism, and which activation elicits a wide array of biological responses. While a number of studies have been dedicated to FXR signaling in liver repair processes, TGR5 remains poorly explored in this context. Because of the massive and potentially harmful BA overload that faces the remnant liver after partial ablation or destruction, both BA-induced adaptive and proliferative responses may stand in a central position to contribute to the regenerative response. Based on the available literature, both BA receptors may act in synergy during the regeneration process, in order to protect the remnant liver and maintain biliary homeostasis, otherwise potentially toxic BA overload would result in parenchymal insult and compromise optimal restoration of a functional liver mass., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Hepatic artery thrombosis (HAT) is the most severe vascular complication occurring after liver transplantation, with an incidence ranging from 2 to 9% in adults. Although the ideal arterial reconstruction is often described as a short and non-redundant anastomosis fashioned between the recipient and donor hepatic arteries, there is no strong evidence about this ideal reconstruction in the literature. The aim of this study was to assess the impact of the type of arterial reconstruction on early HAT after primary liver transplantation., Methods: We retrospectively reviewed a contemporary MELD era cohort of 282 patients who underwent deceased donor primary liver transplantation from 2007 to 2012. Graft artery was classified as "short" when the section was located at the proper/common hepatic artery or "long" when the celiac trunk was used for anastomosis. Recipient arterial sites for arterial anastomosis were classified in three sites: (1) "distal" (proper hepatic artery or common hepatic artery/gastro-duodenal bifurcation), (2) "intermediate" (common hepatic artery) and (3) "proximal" (celiac trunk-splenic artery-aorta). We used univariate and multivariate analyses to assess the impact of different types of arterial reconstruction on early HAT., Results: Of 282 primary liver transplantations, 17 patients (6%) developed early HAT. Patients with and without early HAT had comparable demographic and operative data. The main anastomotic combination was short graft artery on the recipient-common hepatic artery (n = 111, 39%). A long graft artery was used in 91 patients (32%) and was associated with hepatic artery variations (56%; n = 51; p = 0.001). Arterial reconstructions using a long graft artery (p = 0.003), a recipient proximal site as celiac trunk-splenic artery-aorta (p = 0.02) and the combination of a long graft artery on the recipient distal hepatic artery (p = 0.02) were significantly associated with early HAT. The early HAT rate in patients with a long graft artery was not significantly different between patients with or without donor arterial variation (respectively, 12% (n = 6/51) vs. 12% (n = 5/40); p = 1). In multivariate analysis, the use of a long graft artery, whatever the recipient anastomosis site, was an independent risk factor of early HAT (OR 3.2; 95% CI 1.2-9; p = 0.02)., Conclusion: The type of arterial reconstruction used for arterial anastomosis during primary liver transplantation has an impact on the occurrence of early HAT. The use of a long graft artery is an independent risk factor of early HAT. Thereby, we recommend the use of a short graft artery with a direct path when feasible to reduce the occurrence of early HAT after primary liver transplantation.

Liver biopsy is still useful in selected clinical situations in which it is the only tool to obtain information necessary for the diagnosis, the prognosis, and the decision for treatment. Main examples are viral hepatitis with confounding co-morbidities, non alcoholic fatty liver disease, and autoimmune liver diseases.

The last thirty years have been very prosperous in the field of liver transplantation (LT), with great advances in organ conservation, surgical techniques, peri-operative management and long-term immunosuppression, resulting in improved patient and graft survival rates as well as quality of life. However, substance addiction after LT, namely alcohol and tobacco, results in short term morbidity together with medium and long-term mortality. The main consequences can be vascular (increased risk of hepatic artery thrombosis in smokers), hepatic (recurrent alcoholic cirrhosis in alcohol relapsers) and oncological (increased risk of malignancy in patients consuming tobacco and/or alcohol after LT). This issue has thus drawn attention in the field of LT research. The management of these two at-risk behaviors addictions need the implication of hepatologists and addiction specialists, before and after LT. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, give practical tools for identification of high risk patients and treatment options., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Alcohol relapses after liver transplantation (LT) constitute a critical issue. Because there is no widely accepted definition of LT, its prevalence varies from 7 to 95% across studies. Only a severe relapse, the frequency of which is estimated to be 11 to 26%, decreases life expectancy after 5 years of LT and requires specific care. To improve the early identification of alcohol consumption among transplanted patients, liver transplant teams may be helped by input from an addiction team. Nevertheless, added benefit of involvement by addiction specialists in treating posttransplant patients has not been demonstrated. Thus, the aim of this study was to compare the evaluation of the alcohol consumption after LT performed routinely during the transplant consultation or obtained from a specific addiction consultation., Methods: This was a prospective single-site study. Patients were seen consecutively by their hepatologist and by an addiction specialist, and they completed the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). Thus, the patient's alcohol status was assessed using 3 different sources of information: the hepatologist's interview, the AUDIT-C score, and the addiction specialist visit., Results: One hundred forty-one patients were consecutively evaluated. Alcohol consumption was identified by the hepatologist in 31 patients (21.9%), in 52 (36.8%) using the AUDIT-C questionnaire, and in 58 (41.1%) by the addiction specialist. The 31 patients concerned reported an average of 6.5 alcohol units/wk to the transplant physician, a number which was significantly greater (p = 0.001) by 8.6 units/wk when they were interviewed by the addiction specialist., Conclusions: This study highlights the clinical utility of a systematic addiction consultation among liver transplant patients, irrespective of the reason for transplantation., (Copyright © 2016 by the Research Society on Alcoholism.)

Liver transplantation has been the treatment of choice for end-stage liver disease since 1983. Cancer has emerged as a major long-term cause of death for liver transplant recipients. Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers post-liver transplantation; some have also studied risk factors. Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers. Risk of head and neck, lung, esophageal, cervical cancers and Kaposi's sarcoma is high, but risk of colorectal cancer is not clearly demonstrated. There appears to be no excess risk of developing breast or prostate cancer. Environmental risk factors such as viral infection and tobacco consumption, and personal risk factors such as obesity play a key role, but recent data also implicate the role of calcineurin inhibitors, whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis. In this paper, we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and, ultimately, discuss how to prevent these cancers. Immunosuppressive protocol changes, including a calcineurin inhibitor-free regimen, combined with dietary guidelines and smoking cessation, are theoretically the best preventive measures.

The use of liver transplantation (LT) as a treatment for alcoholic liver disease (ALD) has been highly controversial since the beginning. The ever increasing shortage of organs has accentuated the low priority given to patients suffering from ALD, which is considered a "self-inflicted" condition. However, by improving the long-term survival rates, making them similar to those from other indications, and recognizing that alcoholism is a primary disease, ALD has become one of the most common indications for LT in Europe and North America, a situation thought unfathomable thirty years ago. Unfortunately, there are still many issues with the use of this procedure for ALD. There are significant relapse rates, and the consequences of excessive drinking after LT range from asymptomatic biochemical and histological abnormalities to graft failure and death. A minimum three-month period of sobriety is required for an improvement in liver function, thus making LT unnecessary, and to demonstrate the patient's commitment to the project, even though a longer abstinence period does not guarantee lower relapse rates after LT. Recent data have shown that LT is also effective for severe alcoholic hepatitis when the patient is unresponsive to corticosteroids therapy, with low relapse rates in highly selected patients, although these results must be confirmed before LT becomes a standard procedure in this setting. Finally, LT for ALD is accompanied by an increased risk of de novo solid organ cancer, skin cancer, and lymphoproliferative disorders, which has a large impact on the survival rates.

Background & Aims: Increased rates of solid organ cancers post-liver transplantation have been reported, but the contribution of environmental factors and immunosuppressive therapy is not clear. This study's aims were to compare the incidence of de novo solid organ cancers after liver transplantation; identify risk factors independent of immunosuppressive therapy associated with these cancers; and assess the influence of calcineurin inhibitors on the appearance of these cancers., Methods: This single-centre study from 1991 to 2008 included 465 liver recipients who had survived for ≥1 year. Gross incidence rates were standardized by age and sex, using the global population as a reference. In addition, 322 of the 465 patients treated for ≥1 year with calcineurin inhibitors were studied., Results: Sixty-five (13.9%) of the 465 patients developed de novo solid cancers. The overall relative risk was 3.7. Significantly increased relative risks were observed for digestive, oesophageal, colorectal, oral and lung cancers, but not for genito-urinary and breast cancers. Among the 65 patients who developed solid organ cancers, 43 died (66.1%), 41 from cancer. The two independent risk factors were pretransplant smoking [P < 0.0001; odds ratio = 5.5 (.5; 12)] and obesity [P = 0.0184; odds ratio = 2.2 (1.1; 4.3)]. Of the 322 patients on calcineurin inhibitors, 55 (17%) developed de novo solid cancers. Tacrolimus exposure level was a risk factor for de novo solid cancers [P < 0.0001; OR = 15.3 (4.5; 52.2)]., Conclusions: We recommend a change in immunosuppressive protocols with lifestyle/dietary guidelines and smoking cessation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)