Background Combined heart-liver transplantation (CHLT) offers new possibilities for patients with no other treatment options, yet it remains a rare and complex procedure. Despite an increase in its utilisation in recent years, data remain scarce, and many aspects of the procedure are not yet fully understood, particularly the causes of its significant perioperative morbidity, such as acute kidney injury. The CARDHEPAT study presents the first description of a French regional cohort of CHLT patients. Methods A retrospective analysis of the CARDHEPAT cohort examined 30 CHLTs performed at Assistance Publique - Hôpitaux de Paris (APHP) from January 1, 2002, to January 1, 2022. The aim of this study was to highlight the impact of postoperative KDIGO3 acute kidney injury (AKI) on recipient outcomes and its evolution. Results KDIGO3 AKI was observed in 50% of cases and was associated with an excess mortality rate among patients undergoing CHLT. At Day-30 and -90, the survival rates with KDIGO3 AKI were 67% and 53%, respectively, compared to 100% and 93% in patients without (p=0.04 and p=0.03). Additionally, we found several intraoperative factors that were associated with the occurrence of postoperative KDIGO3 AKI, including durations of extracorporeal circulation and aortic clamping and level of intraoperative acidosis but also preoperative albuminemia Conclusion The incidence of KDIGO3 AKI is high after CHLT and seems to be associated with increased mortality, with results suggesting that the intraoperative phase is crucial for its occurrence.

Background & Aims: Fontan-type surgery is a palliative procedure for congenital heart disease with univentricular physiology that may, in the long term, lead to advanced chronic liver disease. Herein, we assessed the accuracy of conventional non-invasive models for assessing liver fibrosis in the context of Fontan circulation and developed a new risk score employing non-invasive tools. Methods: A prospective, cross-sectional, observational study was conducted across five European centers and encompassing all consecutive adult patients with Fontan circulation, liver biopsy and non-invasive tests (e.g. elastography, APRI, and FIB-4). The primary outcome was the identification of severe liver fibrosis on biopsy. Multivariable logistic regression identified non-invasive predictors of severe fibrosis, leading to the development and internal validation of a new scoring model named the FonLiver risk score. Results: In total, 217 patients (mean [SD] age, 27.9 [8.9] years; 50.7% males) were included. Severe liver fibrosis was present in 47.9% (95% CI 41.2%-54.5%) and correlated with a lower functional class, protein-losing enteropathy, and compromised cardiopulmonary and systemic hemodynamics. The final FonLiver risk score incorporated liver stiffness measurement using transient elastography and platelet count, and demonstrated strong discrimination and calibration (AUROC of 0.81). The FonLiver risk score outperformed conventional prediction models (e.g. APRI and FIB-4), which all exhibited worse performance in our cohort (AUROC <0.70 for all). Conclusion: Severe liver fibrosis is prevalent in adults following Fontan-type surgery and can be effectively estimated using the novel FonLiver risk score. This scoring system can be easily incorporated into the routine assessment of patients with Fontan circulation. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Light Chain Deposition Disease (LCDD) is a rare monoclonal gammopathy characterized by deposition of light chains along the basement membranes of various organs, leading to progressive dysfunction (1,2). It has histological features that differ from amyloidosis and is most often characterized by the overproduction of kappa light chains (2). The kidney is usually the most affected organ and is responsible for the initial clinical manifestations, whereas liver dysfunction is less common and generally less severe than kidney involvement (1,3). We present a case of LCDD in a patient with renal dysfunction associated with secondary sclerosing cholangitis (SSC) and severe liver and kidney involvement, efficiently treated with autologous stem cell transplantation followed by double liver-kidney transplantation.

BACKGROUND AND AIMSA recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection.METHODSWe conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal.RESULTSWe identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n=17) and 39% (n=9) of cases. The events reported were AML (n=22), ALL (n=11), AML and ALL (n=1) and UAL (n=15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL.CONCLUSIONThis study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.

In current guidelines, liver transplantation (LT) should be considered in patients with early-stage hepatocellular carcinoma (HCC) because of their lower risk of recurrence and excellent long-term overall survival (OS). To broaden curative opportunities in intermediate and advanced HCC, downstaging strategies are emerging and associated with similar OS compared to patients initially meeting LT criteria. These strategies may however expose these patients to higher HCC recurrence risk. HCC recurrence post LT is essentially metastatic and extrahepatic, and these patients’ prognosis is very poor. The treatments used in this case are tyrosine kinase inhibitors (TKIs) with a low response rate and bad tolerance. If immunotherapy is the new standard of care for advanced and metastatic HCC, scarce data about their administration in liver transplanted recipients in case of HCC recurrence are available. As immunosuppressive (IS) treatment and immunotherapy agents share common targets, utilization of immunotherapy in liver recipients remains complex and exposes patients to acute cellular rejection (ACR). We would like to share in this letter our center experience with eight patients that received immunotherapy post LT as long as a standardized specific IS regimen that aims to lower ACR risk and allow immunotherapy to be effective.

Background: Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up. Methods: An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals. Results: A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child–Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed. Conclusions: DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective.

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.

Background Low-phospholipid associated cholelithiasis (LPAC) remains an under-diagnosed condition. It can be revealed by complications such as acute cholecystitis, acute angiocholitis and acute pancreatitis. We report a case of acute pancreatitis secondary to LPAC syndrome. Case presentation A 58-year-old woman was hospitalized for recurrent biliary-type abdominal pain after cholecystectomies. The diagnosis of acute biliary pancreatitis revealing a low-phospholipid associated cholelithiasis syndrome was retained after explorations. An abdominal ultrasound performed by an expert radiologist allowed us to confirm the diagnosis of LPAC syndrome, showing a comet tail image along the intrahepatic bile ducts. Ursodeoxycholic acid was started without waiting for the result of the ABCB4 mutation. The outcome was spectacular with complete disappearance of the symptoms after the first week. Conclusion Expert ultrasound remains the key examination for the confirmation of the diagnosis of a low-phospholipid associated cholelithiasis syndrome. It should be requested at the slightest warning signs such as a young age less than 40 years and recurrence of biliary symptoms after cholecystectomy.

Background and Aims: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1 *28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1 *28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival. Methods: UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations. Results: In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL ( P <0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3–1.7], P =0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin ( P =0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia. Conclusions: In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization.

Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes. However, it is a poorly understood complication, with no consensus for diagnosis. Therefore, HE is often underdiagnosed. Differential diagnosis may be cumbersome because of non-specific symptoms, such as confusion, cognitive disorders, the aetiological factors of cirrhosis and comorbidities, which are often observed in cirrhotic patients. Therefore, an overt or covert form of HE should be systematically investigated. Advice is provided to drive patient work-up. Effective treatments are available to prevent or treat HE bouts, but the issue of single or combination therapy has not been resolved. Transjugular intrahepatic portosystemic shunt (TIPS) placement largely improved the prognosis of cirrhotic patients, but HE occurrence of HE is often a fear, even when post-TIPS HE can be avoided by a careful selection of patients and preventive treatment. HE is an indication of liver transplantation. However, its reversibility post-transplantation and the consequences of transplantation in patients with other causes of neurological disorders remain controversial, which supports the performance of an extensive work-up in expert centres for this subset of patients. The present guidelines assist clinicians in the diagnosis of the overt or covert form of HE to implement curative and preventive treatments and clarify which patients require referral to expert centres for consideration for liver transplantation. These guidelines are very clinically oriented and address different frequent clinical issues to help physicians make bedside decisions.

Background: While abnormalities of liver function and imaging are common in patients with end-stage heart failure, advanced fibrosis is uncommon. Liver biopsy (LB) is used to identify advanced fibrosis in heart transplant (HT) candidates but can delay or limit access to definitive therapies and cause complications. We sought to develop and determine the utility of a clinical risk score for advanced fibrosis in HT candidates. Methods: We conducted a retrospective, single-center review of patients evaluated for HT between 2012 and 2019 (n = 1,651) and identified those who underwent LB (n = 137) as well as a matched control cohort (n = 160). All biopsies were reviewed by a liver pathologist. Kaplan-Meir curves were used to assess survival. Univariate logistic modeling was used to identify factors predictive of advanced liver fibrosis. Simulation using synthetic data bootstraps was performed to determine the utility of using a score-based approach to trigger LB. Results: We identified 32 (23%) patients with stage 0, 79 (58%) with stage 1-2, and 26 (19%) with stage 3-4/advanced fibrosis. We found no difference in survival at 3 years post-HT based on pre-HT fibrosis stage. The factor most associated with pursuit of LB was abnormal liver parenchyma on ultrasound. We found that a score combining severe tricuspid regurgitation, alcohol use, and low-density lipoprotein improved specificity and reduced the number of LBs required. Conclusions: A score composed of non-invasive factors may help reduce the number of patients who require LB for diagnosis of advanced fibrosis. Additional multicenter studies are needed to validate this score.

Intravenous (IV) hepatitis B immunoglobulin (HBIg) following liver transplantation reduces graft loss attributable to hepatitis B and D virus (HBV, HDV) recurrence. At-risk patients still require long-term HBIg treatment, which is inconvenient and costly. We investigated the long-term feasibility of switching to tailored, low dose, self-administered subcutaneous (SC) HBIg in high-risk patients stabilized on IV HBIg plus nucleotide analog therapy. Patients with liver transplantation and at high risk of HBV recurrence were enrolled in a patient education program (PEP). Treatment with SC HBIg 500 IU every 15 days was started 1 month after the last dose of IV HBIg. Injections were administered by patients at home following instruction. Dosage was tailored to maintain HB surface antibody levels >50 or 100 IU/L, depending on risk profile. Patients’ skills acquisition, satisfaction and adherence were assessed. HB surface antigen, HBV DNA and alanine aminotransferase were monitored regularly. Budget impact was assessed by comparing the direct costs of 3 years’ treatment with IV versus SC HBIg for each patient. Ten patients were prospectively enrolled. Mean time since transplantation was 6.8 years. By year 3, no cases of HBV recurrence and no treatment-related adverse events occurred. The PEP was associated with high levels of skills acquisition, satisfaction, and adherence to treatment. Switching from IV to SC HBIg led to a 56% reduction in annual direct costs per patient. Trained, high-risk patients receiving IV HBIg can successfully and satisfactorily switch to long-term self-administered SC HBIg treatment, markedly reducing direct costs.

Background Acute cellular rejection beyond the 6th month posttransplant is an uncommon complication after liver transplantation. The inadequate immunosuppression (IS) remains the main risk factor. We report a case of acute cellular rejection after a switch to everolimus monotherapy at 11 months following liver transplantation. Case presentation This was a 69-year-old man who underwent liver transplantation after hepatocellular carcinoma. The initial immunosuppression was a combination of three immunosuppressive drugs (corticosteroids + tacrolimus + mycophenolate mofetil). The corticosteroid therapy was stopped at the 4th month posttransplant. Serious side effects of the immunosuppressive drugs (agranulocytosis and renal dysfunction), which occurred 4 months after transplantation, required a reduction and then a discontinuation of tacrolimus and mycophenolate mofetil. Everolimus was introduced as a replacement. The patient was consulted at 11 months after liver transplantation, 1 month after stopping the two immunosuppressive drugs, for liver function test abnormalities such as cytolysis and anicteric cholestasis. A moderate late acute cellular rejection was confirmed by a liver biopsy. A satisfactory biological evolution was observed following corticosteroid boluses and optimization of basic immunosuppressive drugs. Conclusion Late acute cellular rejection remains an uncommon complication, observed mostly in the first year after liver transplantation. The main risk factor is usually the decrease of immunosuppression.

Background: After several cases of peculiar hematological malignancies following introduction of new oral anti-hepatitis C virus (HCV) treatments in our recent practice, we aimed to systematically identify all cases of hematological malignancies (HM) in patients with chronic HCV infection and to compare them according to the prescription of oral anti-HCV Direct Acting Antivirals (DAA) treatment or not. Material/methods: In this single-center retrospective observational study, we included all patients with confirmed HM and chronic HCV infection managed between 2010 and 2019 in the Pitie-Salpetriere hospital, Paris. Non-inclusion criteria were a benign hematological disorder, an & nbsp;HM preceding chronic HCV infection and HCV acute infection. We compared characteristics of patients who received DAA before HM diagnosis to those with no DAA before HM. Results: Over the 10 years, 61 cases of HM among HCV infected patients were identified (female 29%, median age of 58.0 years [IQR 17]). Twenty-one received DAA before the onset of HM (Group DAA+) and 40 did not (Group DAA-) including 22 having received DAA after HM. In the DAA+ group, oral NS5B, NS5A and NS3A inhibitors were used in 90, 76 and 29% respectively. HM developed in the two years following DAA initiation in 76%. Eight (38%) had Non-Hodgkin Lymphoma, 5 (24%) had an Acute Myeloid Leukaemia (AML) including two with a mixed phenotype, 2 each had Hodg-kin Lymphoma, Multiple Myeloma or a myeloproliferative disorder and one each had a chronic Lymphocytic Leukaemia or AL Amyloidosis. In the Group DAA-, HM were NHL in 20(50%) patients, Myeloproliferative neoplasms in 7 (17%), Multiple Myeloma in 5, Hodgkin Lymphoma in 3, Myelo-dysplastic syndrome and AML in 2 (5%) each and Acute Lymphoblastic Leukaemia in one. No sig-nificant difference between the groups DAA + and -was found according to age, sex, HCV genotype, viral load, co-infection or type and exposition of previous HCV treatments. AML, liver transplantation and cirrhosis were significantly more frequent in the DAA+ group (p = 0.020, 0.045 and 0.032, respectively). Conclusion: AML seemed more frequent after using DAA treatments, notably in severe HCV patients including cirrhotic and/or liver transplanted patients. A multicentric observational study is ongoing to confirm and explore the results. (c) 2022 Elsevier Masson SAS. All rights reserved.

Introduction: Hepatitis C virus (HCV) may recur after liver transplantation (LT) in the severe form of fibrosing cholestatic hepatitis (FCH). The prognosis dramatically improved by the use of direct acting antivirals (DAAs). The aim of the present study was to describe the change in histo-logical features of FCH after virological eradication.Methods: From the ANRS CUPILT cohort we included 17 patients who presented FCH and at least two graft biopsies, one before DAA-treatment and one after. A single expert pathologist, blinded for clinical outcome, retrospectively confirmed the diagnosis of FCH and progression of fibrosis.Results: Diagnosis of FCH was made after a median [IQR] 6.0 [3.1-11.8] months after LT, and the median interval between diagnosis and onset of treatment was 1.2 [0.7-6.1] months. The rate of viral eradication was 94.1%. The median delay between the pre-treatment and the treatment biopsies was 12.5 [11.1-20.0] months. Between the end of treatment and the second biopsy, the delay was 5.3 [0.6-7.4] months. Fibrosis stage worsened in 10 patients (58.8%); 6 patients had cirrhosis (35.3%). Chronic rejection appeared in 4 (23.5%) patients.Conclusion: Our results suggest that, despite viral eradication in patients presenting FCH after LT, fibrosis progression was observed in half of patients. This should encourage monitoring fibrosis progression despite HCV cure.(c) 2022 Published by Elsevier Masson SAS.