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Liver involvement in SCD patients is frequent but often misdiagnosed or underestimated, except in case of advanced liver diseases. Because of so far poorly recognized forms of chronic SCD-related vascular injury that can silently evolved towards end stages or facilitate ACLF, any persisting liver function tests abnormalities should be carefully investigated, following the above proposed algorithm. Work up and management must be considered multidisciplinary in relationship with a Hepatologist. Early SCD hepatopathy should prompt revision of SCD management to prevent further liver injury and decompensation, discussing transfusion exchanges and hydro urea when not yet initiated, and control for any cofactor of liver injury. The role of HSCT in early SCD hepatopathies also deserves evaluation. In advanced SCD hepatopathies, liver transplantation, which has been rarely performed so far, is the only therapeutic option associated with improved survival. It should definitely be discussed- either electively in case of decompensation in SCD cirrhosis or jaundice/recurrent cholangitis in cholestatic diseases, with excellent outcome, - or emergently in case of ALF or ACLF with more mitigate results. To improve knowledge and management of SCD liver diseases, creation of national and international registries, as well as longitudinal observational cohorts are encouraged., Competing Interests: Disclosure of Interest The authors declare that they have no competing interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Direct-acting antivirals (DAA) has dramatically improved the prognosis of liver transplantation (LT) candidates for HCV end-stage liver disease (ESLD). We aimed to evaluate the impact of DAA on waiting list (WL) registration and LT activity in France. We evaluated all patients registered to the French WL for HCV ESLD between 2000 and 2018. Timespan was divided into two periods according to DAA availability: 2010-2013 versus 2014-2018. Changes in the indications of LT, outcome on WL were evaluated. Then, we evaluated the activity of LT and outcome for HCV recipients in France. Among 3,173 HCV candidates, registration on WL decreased by 33% between 2013 and 2018. The 1-year waitlist survival increased from 76.9% (95%CI: 74.2%-79.4%) in 2010-2013 to 79.8% (95%CI: 77.2%-82.1%) in 2014-2018 (p < 0.01). Regarding LT activity, the part of HCV ESLD decreased from 26% in 2010 to 16% in 2018. The 1-year graft survival rate in HCV recipients increased from 76.9% (95%CI: 73.7%-79.7%) in 2010-2012 to 84.9% (95%CI: 82.9%-86.7%) in 2013-2018 (p < 0.01). The availability of DAA to treat HCV infection is associated with a significant decrease of registration for LT, death and drop out for worsening condition on the LT. In addition, it has decreased the number of HCV+ LT and improved the 1-year graft survival in France., Competing Interests: Declaration of Competing Interest There is no conflicts of interest, (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Liver transplantation remains the only treatment for terminal liver diseases. However, immunosuppressive drugs required for allograft acceptance are toxic and may be responsible for severe side effects. Modulating the immune system to induce tolerance is a promising approach to reduce immunosuppressive regimen. More particularly, promoting natural CD4 + CD25 + FoxP3 + Tregs could be crucial in achieving tolerance. Contrary to calcineurin inhibitors, reports indicate that mTOR inhibitors may have a positive impact on Tregs. Here we present the first randomized prospective clinical study where Tregs levels from liver transplanted patients receiving either tacrolimus or everolimus were monitored for 6 months, starting from the day of transplantation. A total of 30 patients from four centers were monitored. Blood samples were obtained at day 0, day 14, one month, three months and six months post-transplantation. Flow-cytometry immunophenotyping of Tregs (CD4 + CD25 + CD127 - FoxP3 + ) and functional assays with Tregs were performed to assess their immunosuppressive capacity. Levels of Tregs were significantly reduced after one month of standard tacrolimus-based immunosuppressive regimen (p<0.05). Four months after conversion, levels of Tregs from patients treated with everolimus was significantly higher than patients under tacrolimus (p<0.02). Functional assays demonstrated that Tregs conserved their capacity to suppress the proliferation of activated PBMC., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: After liver transplantation (LT),de novo malignancies are one of the leading causes of late mortality. The aim of the present retrospective study was to identify the risk factors of de novo malignancies in a large cohort of LT recipients in France, using Fine and Gray competing risks regression analysis., Methods: The study population consisted in 11004 adults transplanted between 2000 and 2013, who had no history of pre-transplant malignancy, except primary liver tumor. A Cox model adapted to the identification of prognostic factors (competitive risks) was used., Results: From the entire cohort, one (or more)de novo malignancy was reported in 1480 L T recipients (13.45%). The probability to develop a de novo malignancy after LT was 2.07% at 1 year, 13.30% at 5 years, and 28.01% at 10 years. Of the known reported malignancies, the most common malignancies were hematological malignancy (22.36%), non-melanoma skin cancer (19.53%) and lung cancer (12.36%). According to Fine and Gray competing risks regression multivariate analysis, were significant risk factors for post-LT de novo malignancy: recipient age (Subdistribution Hazard Ratio (SHR) = 1.03 95%CI 1.03-1.04), male gender (SHR = 1.45 95%CI 1.27-1.67), non-living donor (SHR = 1.67 95%CI 1.14-2.38), a first LT (SHR = 1.35 95%CI 1.09-1.69) and the type of initial liver disease (alcohol-related liver disease (SHR = 1.63 95%CI 1.22-2.17), primary sclerosing cholangitis (SHR = 1.98 95%CI 1.34-2.91), and primary liver tumor (SHR = 1.88 95%CI 1.41-2.54)). Initial immunosuppressive regimen had no significant impact., Conclusion: The present study confirms that LT recipient characteristics are associated with the risk ofde novo malignancy and this underlines the need for personalized screening in order to improve survival., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in organ transplant recipients remains limited. The aim of this registry-based observational study was to report the characteristics and clinical outcomes of liver transplant (LT) recipients included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19., Methods: COVID-19 was diagnosed in patients who had a positive PCR assay for SARS-CoV-2 or in presence of typical lung lesions on imaging or specific SARS-CoV-2 antibodies. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded., Results: Of the 104 patients, 67 were admitted to hospital and 37 were managed at home (including all 13 children). Hospitalized patients had a median age of 65.2 years (IQR: 58.1 - 73.2 years) and two thirds were men. Most common comorbidities included overweight (67.3%), hypertension (61.2%), diabetes (50.7%), cardiovascular disease (20.9%) and respiratory disease (16.4%). SARS-CoV-2 infection was identified after a median of 92.8 months (IQR: 40.1 - 194.7 months) from LT. During hospitalization, antimetabolites, mTOR inhibitor, and CNIs were withdrawn in 41.9%, 30.0% and 12.5% of patients, respectively. The composite endpoint of severe Covid-19 within 30 days after diagnosis was reached by 33.0% of the adult patients. The 30-day mortality rate was 20.0%, and 28.1% for hospitalized patients. Multivariate analysis identified that age was independently associated with mortality., Conclusion: In our large nationwide study, Covid-19 in LT recipients was associated with a high mortality rate., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background and Aims: In this French multicentre, open-label study, we analyzed the efficacy, safety and patient-reported outcomes of a boceprevir-based triple therapy in HCV genotype 1 cirrhotic patients awaiting liver transplantation (LT)., Methods: Patients received PEG-IFN/ribavirin (RBV) for 48 weeks (W) and boceprevir from W4 to W48 or until LT., Results: Fifty-one patients (80% males, median age: 56 years) were included. Fifty-seven percent had hepatocellular carcinoma and 43% end-stage liver disease. At enrolment, the median MELD score was 9 (range: 6-18); the Child-Pugh score was A in 65%, B in 35% and C in 2%. Therapy was discontinued because of severe adverse events (SAEs) in 39% of cases and virological inefficacy in 24%. 16% of patients had undetectable HCV RNA 24 weeks after the end of treatment (SVR24). LT was performed in 18 patients (35%). HCV RNA was undetectable in 16.6% at LT. Seven patients (14%) died and three deaths were attributed to treatment. SAEs (n=129) were observed in 84% of patients. Twenty-four percent of patients developed severe infections. Albumin<35g/L was independently associated with severe infection. Compared with baseline values, a significant decrease (P=0.02) of the physical dimension of health-related quality of life was observed between W4 and W24. The mean (95% CI) number of self-reported symptoms doubled during treatment (from 6.3 [4.8-7.7] to 11.8 [9.3-14.3]; P<0.001)., Conclusions: The safety of the PEG-IFN/RBV/boceprevir combination is poor in patients awaiting LT, with a high risk of severe infection. Moreover, the limited efficacy confirms the indication for IFN-free combinations in these patients., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background and Aims: There is evidence for an association between thrombosis in the hepatic microcirculation and liver fibrosis. The aim of this study was to evaluate the role of daily low-dose aspirin (75 or 100mg, given for prevention of hepatic artery thrombosis) in fibrosis progression to ≥ F2 fibrosis score in liver-transplant recipients with recurrent hepatitis C virus (HCV)., Methods: All HCV-positive patients who had undergone liver transplantation (LT) between 2000 and 2010 were included. Exclusion criteria were negative HCV RNA, previous LT or death within a year of LT. Liver fibrosis was assessed by histological evaluation. Data were censored at the date of the last histological evaluation before starting anti HCV therapy. Progression to fibrosis F ≥ 2 was analyzed with a multistate model with time-dependent covariables., Results: One hundred and eighty-eight patients were included. In univariate analysis, older recipient and donor age, male donor gender, activity score ≥ A2 after LT, number of steroid boluses and aspirin intake (HR: 0.75 [0.57-0.97]; P=0.03) influenced the risk of progression to fibrosis ≥ F2. In multivariate analysis, adjusted on site, older donor age, male donor gender, activity score ≥ A2 and number of steroids boluses, remained independent predictors of fibrosis progression, while younger recipient age and aspirin intake (HR: 0.65 [0.47-0.91]; P=0.01) were associated with a slower fibrosis progression., Conclusion: Low-dose aspirin treatment might be associated with a lower risk of liver fibrosis progression in patients with HCV recurrence after LT., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Recurrent hepatitis C after liver transplantation (LT) is associated with rapid fibrosis progression. The aim of this study was to evaluate the cumulative risk for severe fibrosis and the factors influencing it., Patients and Methods: Two hundred and fifty LT patients were included 1 to 15years after LT. Recurrence of chronic hepatitis C on liver graft was classified according to Metavir score., Results: Kaplan-Meyer estimates for actuarial progression to severe fibrosis (Metavir>F3) showed a probability of 15.2% and 44.5% at 5 and 10years, respectively. Predictive factors for progression to severe fibrosis were: use of tacrolimus as main CNI, recipient age at time of biopsy<55, donor age ≥45, graft HCV re-infection<3months, biologically suspected graft re-infection and lack of response to antiviral treatment after LT. Multivariate analysis disclosed that only donor age ≥45 (hazard ratio 2.243, 95%CI 1.264-3.983, P=0.0058) and lack of response to antiviral treatment (hazard ratio 2.816, 95%CI 1.227-6.464, P=0.0146) were associated to severe fibrosis., Conclusions: Our study confirms that donor age ≥45 and lack of response to antiviral treatment after LT are major predictive factors of progression of HCV recurrence on liver graft., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Liver stiffness measurement (LSM) by transient elastography (TE) (FibroScan) is a validated method of quantifying liver fibrosis in non-transplanted patients with hepatitis C virus (HCV). It could be useful in follow-up after liver transplantation (LT). The aim of this study was to assess the diagnostic accuracy of LSM in evaluating liver fibrosis after LT in patients with and without recurrent HCV., Patients and Methods: Forty-three patients (mean age 57.6 ± 9.9 years), 28 (65.1%) HCV-positive patients and 15 (34.9%) HCV-negative patients underwent gold standard liver biopsy and TE 55.8 ± 4.9 months after transplantation. Liver fibrosis was scored on biopsy specimens according to METAVIR (F0-F4). Accuracy of TE and optimal stiffness cut-off values for fibrosis staging were determined by a receiver-operating characteristics (ROC) curve analysis., Results: Median stiffness values were significantly different for METAVIR score less than 2 (5.8 kPa) vs. METAVIR score greater to equal to 2 (9.6 kPa) (P<0.001). The area under the ROC curve was 0.83 for METAVIR score greater to equal to 2 (95%CI: 0.71-0.95). The optimal stiffness cut-off value was 7 kPa for METAVIR scores greater to equal to 2. The results were similar whether the patients had recurrent HCV infection or not., Conclusions: These results indicate that transient elastography accurately identifies LT recipients with significant fibrosis, irrespective of HCV status. It is a promising non-invasive tool to assess graft fibrosis progression after LT in patients with HCV recurrence, as well as for screening of late graft fibrosis of other etiologies. Transient elastography could reduce the use of invasive protocol biopsies., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Hepatocellular carcinoma (HCC) is currently the leading indication for liver transplantation in France, accounting for 25% of all cases. Transplantation is appropriate, nonetheless, only for patients whose HCC has a low risk of posttransplant recurrence and is limited in size and number, meeting the Milan criteria (1 single nodule of a maximum diameter of 5 cm or 3 lesions of a maximum diameter of 3 cm), or slightly exceeds these criteria without vascular invasion visible on preoperative imaging. Results for this indication are very satisfactory, and 5-year survival ranges from 60 to 80%, according to tumor stage. Small HCCs (<2 cm) are usually treated conservatively. Transplantation is proposed in cases of a contraindication to resection or radiofrequency ablation or of recurrence after local treatment. A history of an extrahepatic tumor is found in approximately 5% of candidates for liver transplantation. This history is not necessarily a contraindication to transplantation. They may be considered eligible for a graft after discussion in a multidisciplinary meeting, if the extrahepatic tumor was treated curatively and if their 5-year tumor-related life expectancy is greater than 50-60%.

Objectives: The objective of this prospective study was to determine whether sociological and/or alcohol-related behavioral factors could be predictive of relapse after orthotopic liver transplantation for alcoholic liver disease., Methods: Fifty-five liver-transplanted patients out of a series of 120 alcoholic cirrhotic patients were enrolled in a randomized prospective study. This study was initially designed to compare the 2 year survival in intent-to-transplant patients versus in-intent-to-use conventional treatment patients. For all patients, an identical questionnaire was completed at inclusion, and every 3 months for 5 years to collect data on alcohol-related behavior factors., Results: Fifty-one patients fulfilled the criteria for the study. The mean follow-up was 35.7 months (range: 1-86). Rate of alcohol relapse was 11% at one year and 30% at 2 years. Alcohol intake above 140 g a week was declared by 11% and 22% of patients at one and 2 years, respectively. The only variable leading to a significantly lower rate of relapse was abstinence for 6 months or more before liver transplantation (23% vs 79%, P=0.0003). This variable was also significant for patients whose alcohol intake was greater than 140 g per week (P=0.003) (adjusted relative risk=5.5; 95%CI=1.3-24.5; P=0.02). Multivariate analysis (Cox model) showed that abstinence for 6 months or more before liver transplantation was the unique predictive variable., Conclusion: In this prospective study of 51 patients transplanted for alcoholic liver disease, abstinence before liver transplantation was the only predictive factor of alcohol relapse after liver transplantation.

All cases of hepatocellular carcinoma reported thus for in patients with nonalcoholic steatohepatitis have occurred on preexisting cirrhosis. We report the case of a 68-Year-old male patient with nonalcoholic steatohepatitis who developed hepatocellular carcinoma in the absence of cirrhosis. This observation suggests a possible relationship between nonalcoholic steatohepatitis and/or excess body weight, and hepatocellular carcinoma independent of cirrhosis. Further epidemiological studies are needed to evaluate the incidence of this association.