Search

Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms.The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD.Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up.Forty-five patients were identified (median age: 49, range: 40-64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser-Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis.In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background and aims: Autoimmune hepatitis (AIH) is a rare indication (

Malignancies are a major cause of late death after liver transplantation (LT). In LT recipients presenting a malignancy, antineoplastic chemotherapy is central part of the therapeutic arsenal, but management of both immunosuppressive and antineoplastic chemotherapy can be very challenging. The aim of the present retrospective study was to describe a recent single center cohort of LT recipients treated with antineoplastic cytotoxic chemotherapy.All LT recipients who received antineoplastic chemotherapy in our center between 2005 and 2021 were included.The study population included 72 antineoplastic chemotherapy courses in 69 patients. There was a majority of men (81.9%); median age at LT was 54.9 (range 1-68) and was 63.0 (18-79) at the diagnosis of malignancy. Lung carcinomas (23.6%), head and neck carcinomas (20.8%), lymphomas (16.7%), and recurrent hepatocellular carcinoma (HCC) (8.3%) were the most frequent malignancies. Neoadjuvant (30.6%), adjuvant (12.5%) or palliative (54.2%) chemotherapy was performed. Immunosuppressive regimen was modified from a calcineurin inhibitor (CNI)-based to an everolimus-based regimen (63.5% of CNI discontinuation). Median survival after diagnosis of malignancy was 22.5 months and 5-year survival was 30.1%. Chemotherapy regimen was considered optimal in 81.9% of the cases. Multivariate analysis disclosed that non-PTLD N+ stage malignancy (HR = 5.52 95%CI [1.40;21.69], p = .014), non-PTLD M+ stage malignancy (HR = 10.55 95%CI [3.20;34.73], p = .0001), and suboptimal chemotherapy (HR = 2.73 95%CI [1.34;5.56], p = .005) were significantly associated with poorer prognosis. No rejection episode occurred during chemotherapy.The present study is the first one focused on antineoplastic chemotherapy in LT recipients. Our results suggest that immunosuppressive drugs and antineoplastic chemotherapy can be managed satisfactorily in most cases but this needs confirmation from larger cohorts.

Determining 24-hour urinary copper excretion (UCE) levels is useful for diagnosing Wilson's disease (WD) and for treatment monitoring. Exchangeable copper (ExC) is a novel potential marker, but its long-term changes have never been described in patients under chelation therapy. Our aim was to describe the long-term changes in ExC levels compared to UCE levels in symptomatic WD pediatric patients under chelation therapy.A retrospective, descriptive, and analytical study including all patients under 18 years of age, diagnosed between 2006 and 2020, and treated with chelation therapy was conducted at the National Reference Center for WD in Lyon. Ceruloplasmin levels, serum copper, 24 h-UCE, ExC, and liver enzymes at diagnosis and during follow-up were analyzed.Our study included 36 patients, predominantly with hepatic form of WD (n = 31). The median [interquartile range (IQR)] age at diagnosis was 10.5 (8.4-13.1) years, and the median (IQR) follow-up duration was 6.3 (3.3-8.8) years. At diagnosis, the median (IQR) ExC value was 1.01 (0.60-1.52) µmol/L. There was a significant decrease during the first year of chelation treatment ( P = 0.0008), then a stabilization. The median (IQR) ExC values was 0.38 (0.22-0.63) µmol/L at 12-18 months and 0.43 (0.31-0.54) µmol/L at 5 years of chelation treatment ( P = 0.4057). Similarly, there was a significant decrease in 24-hour UCE ( Plt; 0.001) during the first year of chelation treatment, then a stabilization.Our study showed a significant decrease in ExC and 24-hour UCE levels during the first year of follow-up; The dynamics of both biomarkers were similar along the follow-up, demonstrating their usefulness in clinical practice for monitoring WD.

Background Superficial oesophageal adenocarcinoma can be resected endoscopically, but data to define a curative endoscopic resection are scarce. Objective Our study aimed to assess the risk of lymph node metastasis depending on the depth of invasion and histological features of oesophageal adenocarcinoma. Methods We retrospectively included all patients undergoing an endoscopic resection for T1 oesophageal adenocarcinoma among seven expert centres in France in 2004–2016. Mural invasion was defined as either intramucosal or submucosal tumours; the latter were further divided into superficial submucosal (1000 mm). Absence or presence of lymphovascular invasion and/or poorly differentiated cancer (G3) defined a low‐risk or a high‐risk tumour, respectively. For submucosal tumours, invasion depth and histological features were systematically confirmed after a second dedicated histological assessment (new 2‐mm thick slices) performed by a second pathologist. Occurrence of lymph node metastasis was recorded during the follow‐up from histological or PET CT reports when an invasive procedure was not possible. Results In total, 188 superficial oesophageal adenocarcinomas were included with a median follow‐up of 34 months. No lymph node metastases occurred for intramucosal oesophageal adenocarcinomas (n = 135) even with high‐risk histological features. Among submucosal oesophageal adenocarcinomas, only tumours with lymphovascular invasion or poorly differentiated cancer or with a depth of invasion >1000 μm developed lymph node metastasis tumours (n = 10/53%; 18.9%; hazard ratio 12.04). No metastatic evolution occurred under a 1000‐mm threshold for all low‐risk tumours (0/25), nor under 1200 mm (0/1) and three over this threshold (3/13%, 23.1%). Conclusion Intramucosal and low‐risk tumours with shallow submucosal invasion up to 1200 mm were not associated with lymph node metastasis during follow‐up. In case of high‐risk features and/or deep submucosal invasion, endoscopic resections are not sufficient to eliminate the risk of lymph node metastasis, and surgical oesophagectomy should be carried out. These results must be confirmed by larger prospective series., Key Summary Superficial oesophageal adenocarcinoma (OAC) can be resected endoscopically.Data to define a curative endoscopic resection with a low lymph node metastasis (LNM) risk are scarce especially for tumours invading the submucosa.Curative endoscopic resections have been reported in selected OAC invading the first 500 mm of the submucosa, but surgical series showed an LNM risk ranging from 0% to 50%, making endoscopic resection a questionable curative treatment.High‐risk histological features were not associated with LNM in intramucosal tumours.LNM occurred only for tumours invading the submucosa with a depth ≥1200 mm or with high‐risk histological features regardless of the depth of invasion.Endoscopic resection may be a valid and curative therapeutic option for all intramucosal tumours and for submucosal oesophageal adenocarcinoma with an invasion depth ≤1000 mm and low‐risk histological features.

Resume En France, on estime entre 1000 et 1500 le nombre de patients atteints de maladie de Wilson (MW). C’est une affection monogenique de transmission autosomique recessive dont le gene est localise sur le chromosome 13. La MW est caracterisee par une accumulation excessive de cuivre dans l’organisme initialement dans le foie puis dans d’autres organes (cerveau, cornee, globules rouges), evoluant vers une affection systemique. La plupart des patients pediatriques atteints de MW presentent une maladie du foie alors que les symptomes neuropsychiatriques sont plus frequents chez les adultes. La MW peut se presenter a tout âge. Le screening familial est indispensable. Une fois le diagnostic evoque, le bilan cuprique et, en particulier l’etude du ratio cuivre echangeable/cuivre total (REC) plasmatique (test rapide et sensible), permet en regle generale une confirmation du diagnostic avec en parallele la recherche de mutations du gene ATP7B qui se revele positive dans 98 % des cas. Les nouveaux traitements par sel de trientine permettent d’adapter la prise en charge des enfants intolerants a la D-penicillamine.

ObjectiveTo evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.MethodsFrench patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.ResultsEighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved (p< 0.0001 andp= 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved (p= 0.0007). Severe sepsis (p= 0.011) and intensive care unit admission (p= 0.001) before LT were significantly associated with death.ConclusionsLT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.Classification of evidenceThis study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.

Background Endoscopic resection has developed over the years. The main complications are perforation and bleeding. This study aimed to evaluate safety and effectiveness of digestive endoscopic resection in patients with cirrhosis. Methods This retrospective, open-label, single-center study included all consecutive patients with cirrhosis who were admitted for endoscopic resection between 2009 and 2016. Safety, efficacy, and risk factors for delayed bleeding were analyzed. Results 126 patients undergoing 164 procedures were included: 65 endoscopic resections (49 patients) in the upper gastrointestinal tract (esophagus 34, stomach 20, duodenum 11) and 99 in the lower gastrointestinal tract (77 patients). Mean Model for End-Stage Liver Disease score was 9.9 (standard deviation 4.5). Esophageal varices were present in 50 patients, and 21 patients had decompensated cirrhosis. The overall curative rate of endoscopic resection was 84.0 %. No patients died during 30-day follow-up. Immediate overall morbidity was 6.1 %, with two postoperative fevers and eight bleeds. Risk factors for delayed bleeding were duodenal location (P Conclusions Endoscopic resection was safe and effective in patients with mild (Child – Pugh class A/B) cirrhosis, and should be proposed as a first option for treatment of superficial neoplasia. Additional data in patients with severe cirrhosis are needed to confirm the safety in this population.

International audience; Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease and alpha-1 antitrypsin deficiency must be investigated in any patient with unexplained liver disease. Cystic fibrosis screening of new-borns is now implemented in most high-prevalence countries. The diagnosis of these diseases can be strongly suggested with specific non-invasive tests. Molecular analysis gene for these diseases is long and tedious but is recommended to confirm the diagnosis and help for the family screening. Liver biopsy is not systematic and is discussed when it helps diagnosis. Currently, for these three diseases, non-invasive fibrosis markers could identify patients with risk of cirrhosis and complications. Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease, must be investigated in any patient with unexplained liver disease and/or unexplained neurological or neuropsychiatric disorders. The diagnosis is based on a combination of clinical, biological features, including copper balance. The exchangeable copper/total copper ratio is a new sensible and specific biological marker, useful for the diagnosis of the disease. Timely diagnosis and treatment will prevent serious complications from the disease. Neurological evaluation and familial screening are essential in patients with Wilson's disease.

OBJECTIVES To describe a cohort of Wilson disease (WD) pediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome. METHODS Clinical data of 182 pediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered. RESULTS Diagnosis of WD was made at a mean age of 10.7 ± 4.2 years (range 1-18 years). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least 1 year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2 μmol/24 hours (0.2-253). The first-line treatment was d-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33 of 39 patients or for neurological deterioration in 6 of 39 patients, mean Unified Wilson's Disease Rating Scale of the latter went from 90 ± 23.1 before liver transplantation (LT) to 26.8 ± 14.1 (P

Liver transplantation (LT) has been proposed as a curative treatment in hereditary hemorrhagic telangiectasia (HHT) with severe hepatic involvement. We provide a long-term evaluation of graft status after LT for HHT, with a focus on the risk of recurrence. The present study included all patients prospectively followed up after LT for HHT in the Lyon Liver Transplant Unit from 1993 to 2010, with a survival of more than 1 year. Protocol clinical, radiological, and histological examinations were performed at regular intervals. Fourteen patients were included (13 women and one man). Median age at LT was 52.5 years (range: 33.1-66.7). In eight patients (seven female), disease recurrence was diagnosed by abnormal radiological features, suggestive of microcirculatory disturbances. Typical vascular lesions, including telangiectasia, were demonstrated by liver biopsy in five of these patients. The median interval between LT and diagnosis of recurrence was 127 months (range: 74-184). The risk of recurrence increased over time; estimated cumulative risk was 47.9% at 15 years. Liver tissue analysis found the coexistence of an angiogenic process combined with endothelial microchimerism, as shown by the presence of vascular lining cells of recipient origin. Conclusion: The present data show that disease recurrence occurs, usually after a long delay, in a significant number of patients treated by LT for liver complications of HHT. This strongly supports the necessity of a lifelong follow-up and suggests that therapeutic strategy needs discussion and evaluation, especially of the role of potential adjuvant treatments to LT, such as antiangiogenic medications, when recurrent disease appears.

Patients having received a liver transplantation (LT) for alcoholic liver disease (ALD) have a high risk of de novo malignancies, especially in the upper aerodigestive tract and lungs due to their smoking and alcohol history. The aim of this retrospective study was to compare a group of patients transplanted for ALD who continue to smoke and who were included in an intensive screening program for tobacco-related cancers implemented at the Grenoble University Hospital and a group of similar patients followed according to usual practice (chest computed tomography [CT] scan every 5 years) at the Edouard Herriot Hospital in Lyon. The intensive screening program consisted of an annual checkup, including a clinical examination by an otorhinolaryngologist, a chest CT scan, and an upper digestive endoscopy. A total of 147 patients were included: 71 patients in Grenoble and 76 patients in Lyon. The cumulative incidence of a first tobacco-related cancer was 12.3% at 3 years, 20.6% at 5 years, 42.6% at 10 years, and 64.0% at 15 years. A curative treatment was possible in 80.0% of the patients in Grenoble versus 57.9% in Lyon (P = 0.068). The rates of curative treatment were 63.6% versus 26.3% (P = 0.062) for lung cancers, 100.0% versus 87.5% (P = 0.498) for lip-mouth-pharynx and larynx cancers, and 66.7% versus 100.0% (P = 1) for esophageal cancers, respectively. In addition, for lung cancers, regardless of study group, 68.7% received a curative treatment when the diagnosis was made by CT scan screening versus 14.3% when it was made because of symptoms (P = 0.008). In conclusion, our study strongly confirms the high rate of tobacco-related de novo malignancies in LT patients for ALD and suggests that the screening of lung cancer by annual chest CT scan could significantly increase the rate of curative treatment.

ObjectiveLiver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.DesignThis international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.ResultsAfter screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.ConclusionThe M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.

Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are rare indications for liver transplantation (LT) in children. The aim of the present retrospective multicenter study was to evaluate long-term outcome after LT for autoimmune liver disease in childhood.Retrospective data from 30 children who underwent a first LT from 1988 to 2018 were collected.The study population consisted of 18 girls and 12 boys, transplanted for AIH type 1 (n=14), AIH type 2 (n=7) or PSC (n=9). Mean age at LT was 11.8±5.2 years. The main indications for LT were acute (36.7%) or chronic end-stage liver failure (63.3%). Graft rejection occurred in 19 patients (63.3%); 6 pts required retransplantation for chronic rejection. Recurrence of initial disease was observed in 6 patients (20.0%), all of them with type 1 AIH, after a median time of 42 months, requiring retransplantation in 2 cases. Overall patient survival rates were 96.4%, 84.6%, 74.8%, 68.0%, 68.0%, 68.0% and 68.0% at 1, 5, 10, 15, 20, 25 and 30 years, respectively. Age at LT1year (p0.0001), LT for fulminant failure (p=0.023) and LT for type 2 AIH (p=0.049) were significant predictive factors of death.Long-term outcome after LT for pediatric autoimmune liver disease is impaired in patients with AIH because of consistent complications such as rejection and disease recurrence.

International audience; Introduction: Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with alpha1 antitrypsin (A1AT) deficiency. The aim of the present retrospective study was to report on long-term outcomes following LT for A1AT deficiency.Methods: The medical records of 90 pediatric and adult patients transplanted between 1982 and 2017 in France and Geneva (Switzerland) were reviewed.Results: The study population consisted of 32 adults and 58 children; median age at transplant was 13.0 years (range: 0.2-65.1), and 65 were male (72.2%). Eighty-two patients (94.8% of children and 84.4% of adults) had the PI*ZZ genotype/phenotype and eight patients (8.9%) had the Pi*SZ genotype/phenotype. Eighty-four patients (93.3%) were transplanted for end-stage liver disease and six (all Pi*ZZ adults) for HCC. Median follow-up after LT was 13.6 years (0.1-31.7). The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years respectively. The overall cumulative graft survival rates were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively.Conclusions: In a representative cohort of patients having presented with end-stage-liver disease or HCC secondary to A1AT, liver transplantation offered very good patient and graft survival rates.

Wilson disease (WD) is an autosomal recessive disorder of copper (Cu) metabolism. The gene responsible for WD, ATP7B, is involved in the cellular transport of Cu, and mutations in the ATP7B gene induce accumulation of Cu in the liver and ultimately in the brain. In a pilot study, the natural variations of copper stable isotope ratios (65Cu/63Cu) in the serum of WD patients have been shown to differ from that of healthy controls. In the present study, we challenged these first results by measuring the 65Cu/63Cu ratios in the blood of treated (n = 25), naïve patients (n = 11) and age matched healthy controls (n = 75). The results show that naïve patients and healthy controls exhibit undistinguishable 65Cu/63Cu ratios, implying that the Cu isotopic ratio cannot serve as a reliable diagnostic biomarker. The type of treatment (d-penicillamine vs. triethylenetetramine) does not affect the 65Cu/63Cu ratios in WD patients, which remain constant regardless of the type and duration of the treatment. In addition, the 65Cu/63Cu ratios do not vary in naïve patients after the onset of the treatment. However, the 65Cu/63Cu ratios decrease with the degree of liver fibrosis and the gradient of the phenotypic presentation, i.e. presymptomatic, hepatic and neurologic. To get insights into the mechanisms at work, we study the effects of the progress of the WD on the organism by measuring the Cu concentrations and the 65Cu/63Cu ratios in the liver, feces and plasma of 12 and 45 week old Atp7b−/− mice. The evolution of the 65Cu/63Cu ratios is marked by a decrease in all tissues. The results show that 63Cu accumulates in the liver preferentially to 65Cu due to the preferential cellular entry of 63Cu and the impairment of the 63Cu exit by ceruloplasmin. The hepatic accumulation of monovalent 63Cu+ is likely to fuel the production of free radicals, which is potentially an explanation of the pathogenicity of WD. Altogether, the results suggest that the blood 65Cu/63Cu ratio recapitulates WD progression and is a potential prognostic biomarker of WD.

Summary Background Biliary complications are the main surgical complication after liver transplantation (LT). The aims of the present retrospective single center study were to describe anastomotic bilio-biliary strictures (ABS) in a large cohort of liver transplant recipients with long follow-up. Methods All adult LT recipients who underwent a LT, with bilio-biliary anastomosis, between 1990 and 2010 in Edouard Herriot hospital, Lyon, France were included in the study. Results The study population consisted in 783 patients (70.0% males), median age 50.5 years; main indication was alcohol-related liver disease (46.8%). The median follow-up after LT was 11.9 years (range 0–27 years). The overall incidence of anastomotic biliary complications was 9.7%: 50 patients developed an ABS (6.6%), after a median delay of 4.4 months (range 0.1–245.2) after LT and 32 (4.1%) developed biliary leakage after a median delay of 25 days (range 1–179). The actuarial risk of developing an ABS was 1.6% at 1-month, 2.7% at 3-months, 4.1% at 6-months, and 5.1%, 6.0%, 6.4%, 6.6%, 7.3% at 1-, 2-, 5-, 10- and 15-years, respectively. Univariate analysis disclosed that post-reperfusion syndrome and liver graft steatosis (≥ 30%) were significant risk factors for ABS. Multivariate analysis disclosed that graft steatosis (OR = 6.262, 95%CI 1.936–20.257, P = 0.002) and MELD score (OR = 1.071, 95%CI 1.018–1.128, P = 0.008) were significant risk factors for ABS. The first-line treatment of ABS consisted in endoscopic stenting for 44 patients (88.0%) and immediate success rate was 75.0%. Delayed recurrence of ABS occurred in 8/33 patients (24.0%). Conclusion Our results suggest that steatotic grafts should be used for recipients without severe liver failure to avoid ABS, and that endoscopic stenting of post-LT ABS leads to a high success rate, but is associated with a significant risk of recurrence.

Background Liver transplantation (LT) is a standard-of-care therapeutic modality for selected patients with life-threatening liver disease, including children. In addition to specific clinical characteristics of pediatric LT recipients due to initial liver disease (and related comorbidities) and level of liver failure, early postoperative outcome may be dependent on the surgical technique used, related to the type of organ donor and graft. Therefore, the aims of the present retrospective study from a large single centre cohort were to identify the prognostic factors for both 1-year patient and graft survival. Methods Between October 1990 and October 2010, 151 children underwent a first LT in our centre. Results The mean age was 5.3 ± 7.4 years, and the main indication was biliary atresia (BA) (49.0%). Living donor liver transplantation (LDLT) was performed in 39 cases (25.8%). Cadaveric liver graft was a whole liver in 50 cases (33.1%) and a partial liver (reduced or split) in 62 cases (41.1%). One-year patient and graft survival rates were 88.7% and 86.1%, respectively. Multivariate analysis disclosed that initial liver disease, location at time of LT, donor/recipient (D/R) delta age, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with patient survival and that D/R delta age, primary non-function, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with graft survival. Conclusion The results of our single-centre experience of pediatric LT emphasize that early patient and graft survivals depend on pre-operative/operative factors such as initial liver disease, D/R delta age and immunosuppressive regimen. Awareness of these factors can help in the decision making for children requiring LT.

International audience; Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR

Background and objective: Symptomatic polycystic liver disease (PLD) with massive hepatomegaly represents a challenging surgical issue. In this work, we focused on early and long term outcomes after partial hepatectomy with cyst fenestration (PHCF) in selected patients. Methods: All patients who had PHCF for treatment of PLD between January 2003 and December 2019 in our center were included in this study. PHCF was undertaken if at least one hepatic section was relatively spared from PLD, afferent and efferent hepatic vasculature was patent, and liver function was maintained. Results: Twenty nine patients (25 women) with a mean age of 54.6±9 years underwent PHCF. Major hepatectomy was performed in all cases with 4.3±0.8 resected segments. Overall perioperative morbidity and mortality rates were 58.6% and 13.8% respectively. Significant postoperative liver volume reduction was 56% during the first year and 65% thereafter. From preoperative evaluation, PS normalized or improved in 80% of patients. After a mean follow-up time of 66.6±66.2 months, overall patient survival was 82.7%. Performance status (PS), initial liver volume, operative time and transfusion were associated with post-operative complications and PS, preoperative cyst infection, portal hypertension, transfusion, postoperative sepsis and persistent ascites were associated with mortality. Conclusions: Our study confirms that in spite of significant morbidity rate, PHCF allows a massive reduction of liver volume in selected patients with symptomatic PLD and is highly and durably effective for the reduction of liver volume and improvement of quality of life.

Summary Background and aims Long-term prognosis after liver transplantation for alcoholic liver disease is impaired because of the occurrence of de novo malignancies and recurrent disease on liver graft. The aim of the present retrospective study was to evaluate the risk of de novo malignancy and to identify the predictive factors in a large cohort of liver-transplanted patients with a long follow-up in the setting of alcoholic liver disease. Methods All patients who underwent a first liver transplantation for alcoholic liver disease in our centre, from December 1985 to October 2010, and who survived more than 6 months were included. Survival, incidence of de novo malignancies and several clinical and biological parameters were studied. Results The study population consisted in 368 patients (284 males, median age 52.6 years). The cumulative incidence of a first solid organ de novo malignancy after LT was 8.7% at 5 years, 22.3% at 10 years, 31.5% at 15 years, and 33.1% at 20 years. Tobacco use (both past and current) was associated with a significant increased risk of de novo solid organ malignancy (HR 3.35 and 4.62, respectively), whereas immunosuppressive regimen including mTOR inhibitors (mTORi) was associated with a decreased risk (post-transplant time under mTORi-including immunosuppressive regimen was significantly longer in patients who did not present de novo malignancy (10.6% vs. 2.3%, P = 1.4 × 10−5)). Conclusions Our study provides additional evidence that de novo malignancies in alcoholic liver disease liver transplant patients is a major long-term complication, and that conversion from to an mTORi-including immunosuppressive regimen could reduce this risk.

International audience; 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.

The incidence and impact of anti-human leukocyte antigen donor-specific alloantibodies (DSAs) developing after liver transplantation (LT) remains controversial and not extensively studied. The aim of the present study was to assess the incidence of DSAs, to identify risk factors for the development of DSAs, and to understand the impact of DSAs in a large population of adult LT recipients. This single-center retrospective study included all adult patients who underwent a first LT between 2000 and 2010 in our center. The study population mainly consisted of male patients, the mean age was 52.4 years, and the main indication was alcoholic cirrhosis (54.1%). From the 297 patients included in the cross-sectional study, 14 (4.7%) had preformed DSAs, and 59 (19.9%) presented de novo DSAs (12.2% at 1 year, 13.4% at 5 years, and 19.5% at 10 years). Multivariate analysis found that female donor sex (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.12-2.01; P = 0.01) and delay between LT and DSA screening (HR, 1.10; 95% CI, 1.01-1.20; P = 0.03) were associated with occurrence of de novo DSAs. From the 190 patients included in the subgroup longitudinal analysis, exposure to tacrolimus (mean trough level during the periods 0-2 years and 0-3 years) was significantly lower for patients having DSAs at 5 years. Concerning histology, only acute rejection (P = 0.04) and portal fibrosis ≥2 (P = 0.02) were more frequent at 1 year for patients with DSAs. Patient survival and graft survival were not significantly different according to the presence or not of DSAs at 1 year. Among the 44 patients who had de novo or persistent preformed DSAs, the diagnosis of antibody-mediated rejection was made in 4 (9.1%) patients after 1, 47, 61, and 74 months following LT. In conclusion, the results of the present study suggest that DSAs are observed in a minority of LT adult patients, with limited overall impact on graft and patient outcome.

Despite systemic thromboembolic complications being frequent, portal vein thrombosis is a rare complication of nephrotic syndrome. We report here a liver transplant recipient who presented a late extensive portal vein thrombosis related to nephrotic syndrome. During regular follow-up after liver transplant, the patient presented with diabetes, arterial hypertension, hypercholesterolemia, and progressive renal dysfunction. In addition, urine analysis showed isolated proteinuria, and the diagnosis of nephrotic syndrome was made 36 months after liver transplant. Sixty months after liver transplant, the patient presented with mild acute abdominal pain, and the diagnosis of portal vein thrombosis was made from a computed tomography scan. Other causes for portal vein thrombosis were excluded. Histologic examination of a liver biopsy disclosed only mild steatosis. Histologic examination of a kidney biopsy disclosed severe lesions, suggesting a multifactorial, advanced chronic nephropathy probably caused by nephroangiosclerosis, diabetes, and toxicity of calcineurin inhibitors. Anticoagulation therapy led to complete recanalization of the portal and splenic veins, which was maintained thereafter. In conclusion, the case we report here illustrates that portal vein thrombosis can occur after liver transplant in the context of nephrotic syndrome, complicating chronic kidney disease, which is a very frequent and multifactorial complication after liver transplant.

The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population.The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate.The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (10,000) had a significant poorer long-term graft survival (p=0.03).In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss.

Background and objective Symptomatic polycystic liver disease (PLD) with massive hepatomegaly represents a challenging surgical issue. In this work, we focused on early and long term outcomes after partial hepatectomy with cyst fenestration (PHCF) in selected patients. Methods All patients who had PHCF for treatment of PLD between January 2003 and December 2019 in our center were included in this study. PHCF was undertaken if at least one hepatic section was relatively spared from PLD, afferent and efferent hepatic vasculature was patent, and liver function was maintained. Results Twenty nine patients (25 women) with a mean age of 54.6 ± 9 years underwent PHCF. Major hepatectomy was performed in all cases with 4.3 ± 0.8 resected segments. Overall perioperative morbidity (Clavien ≥ II) and mortality rates were 41.4.6% and 13.8% respectively. Significant postoperative liver volume reduction was 52.8% within the first year and 55.5% thereafter. From preoperative evaluation, performance status (PS) normalized or improved in 84% of patients. After a mean follow-up time of 70.8 ± 65 months, overall patient survival was 82.7%. In univariate analysis, PS, initial liver volume, operative time and transfusion were associated with post-operative complications and PS, preoperative cyst infection, portal hypertension, transfusion, postoperative sepsis and persistent ascites were associated with mortality. Conclusions Our study confirms that in spite of significant morbidity rate, PHCF allows a massive reduction of liver volume in selected patients with symptomatic PLD and is highly and durably effective for the reduction of liver volume and improvement of quality of life.

Reported hepatotoxicity induced by corticosteroids is very rare, and the diagnosis is highly challenging in the context of auto-immune disease. We report here a case of high-dose methylprednisolone (MP)-induced acute hepatitis confirmed by liver histology in a patient with multiple sclerosis (MS) and a case series (n=4) notified to the French Pharmacovigilance center of Lyon. In all 5 cases, other common causes of hepatitis were excluded. The causal relationship with MP pulse therapy was supported by the fact that MP was the only culprit drug. In addition, 3 of these 5 patients underwent unintended single or multiple positive MP rechallenge. Our 5 patients scored a RUCAM score from 6 (probable) to 10 (highly probable). MP-induced liver injury is probably very rare, since only less than 30 cases have been reported in the literature. Nevertheless, our cases strongly illustrates that many cases could have been unrecognized; final diagnosis in 3 of 5 of our patients was made after the second or third episode of acute hepatitis. In conclusion, these cases we report here strongly illustrates that high-dose MP-induced liver injury can occur in patients treated for MS or auto-immune disorder. Unintended re-challenge can confirm the diagnosis and can help to distinguish it from autoimmune hepatitis. Performing liver function tests routinely both before and after MP administration would be beneficial, as the timely recognition of this complication and early drug withdrawal may prevent progression of severe necrosis hepatic injury.

Hepatocellular carcinoma (HCC) has high recurrence rate after curative treatment. The aim of the present study was to report our experience with adjuvant use of 131I-lipiodol after curative treatment of HCC in terms of recurrence and survival in a large cohort of patients with a long follow-up. All patients treated with 131I-lipiodol after curative treatment of HCC in two French centers from 1991 to 2009 were included in a retrospective cohort study. One hundred and six patients were included. The median (range) follow-up was 6 years (0.3–22). Forty-three patients (41%) had cirrhosis. Recurrence-free survival rates at 1, 2, 5, 10, and 20 years were 73, 57, 40, 30, and 14%, respectively. Cirrhosis was an independent predictive factor of recurrence [RR = 1.18, 95% CI (1.11–3.02), p = 0.019]. Overall, survival rates at 1, 2, 5, 10, and 20 years were 90, 83, 59, 37, and 23%, respectively. Prognostic factors were recurrence [RR = 2.73, 95% CI (1.35–5.54); p = 0.005], age over 60 years (RR = 1.91, 95% CI [1.02–3.61]; p = 0.044), and tumor number over 3 [RR = 3.31, 95% CI (1.25–8.77); p = 0.016]. Our results suggest that the effect of 131I-lipiodol after curative treatment of HCC could be related to a beneficial impact on risk factors of early tumor recurrence. This could be evaluated in further studies using modern radioembolization methods.

Summary Background and aims Portal vein thrombosis (PVT) is a common complication of liver cirrhosis. Anticoagulation therapy is efficient, but is associated with potentially severe side-effects, especially bleeding episodes. It is therefore still unclear which patients will benefit from anticoagulation, and for what duration. The aim of the present study was to retrospectively analyse our single centre experience on long-term anticoagulation in patients presenting a PVT, complicating cirrhosis. Methods Data of 40 cirrhotic patients with PVT treated by anticoagulation therapy from June 2003 to May 2018 were collected. Regular imaging was performed to monitor the outcome of PVT. The hemorrhagic complications and the recurrence of the PVT after anticoagulation withdrawal were also analyzed. Results The median follow-up under anticoagulation therapy was 33.7 months. Complete (57.5%) or partial (25.0%) recanalization of PVT was observed. Fifteen bleeding episodes (37.5%) occurred in our population, related to portal hypertension in 7 (46.7%). Eleven (73.3%) patients required hospitalization and eight (53.3%) required blood transfusion. No patient died from bleeding complication. Anticoagulation was stopped in 10 patients (25.0%), because of regression of PVT in 5 patients or a haemorrhagic episode in 5 patients. Among those 10 patients, 7 had a recurrence or extension of the initial PVT. Conclusions Our results confirm that anticoagulation allows a recanalization of PVT complicating cirrhosis in the majority of the cases, is associated with non-severe bleeding complications, and can be maintained for a long duration in order to avoid recurrence.

International audience

Background Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection. Objective The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients. Methods This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old). Results The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6–39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1–25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17–18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92–0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died. Conclusion The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.

BACKGROUND: Alpha-1-antitrypsin deficiency (A1ATD) is a common genetic condition which predisposes to emphysema and liver disorders. It is estimated that 10-15% of homozygous individuals for the Z allele (PiZZ) may develop liver fibrosis. The optimal modalities to detect liver disease in PiZZ adult patients need to be defined. The aim of this prospective study was to perform a systematic non-invasive evaluation of the liver fibrosis by elastometry using Fibroscan((R)) in a cohort of A1ATD patients with emphysema. METHODS: Patients followed in our respiratory unit were enrolled in this prospective study and underwent on the same day a physical examination, a biochemical profiling, an abdominal ultrasound (US) and a Fibroscan((R)). RESULTS: Twenty-nine PiZZ adults (19 male) were included. Median age was 50.4 yrs (21.5-67.2). Median serum A1AT level was 0.20 g/L (0.15-0.33). Liver Function Tests (LFT) were not normal in 2 patients and US was abnormal in 6 patients. Two patients had both abdnormal LFT and US. Fibroscan((R)) was technically feasible in 28/29 (97%) patients. Median liver stiffness was 4.5 kPa (2.8-32.8), and was \\textgreater 7.2 kPa in 5/28 (18%) and \\textgreater 14 kPa in 2/28 (7%) patients. Liver stiffness was increased in 2/2 (100%) patients with abnormal LFT and US, in 1/4 (25%) with abnormal LFT or US and in 2/22 (10%) patients with normal LFT and US. CONCLUSIONS: Fibroscan((R)) is an easy and repeatable tool which can be used in PiZZ patients to screen for the presence of significant liver fibrosis and to identify patients at higher risk to develop liver complications in the future and who may benefit from a closer surveillance.

Production of de novo DSA (dnDSA) is associated with an increased risk of antibody mediated rejection after liver transplantation. Antibodies not only recognize the entire antigen but are able to bind specific functional epitopes present on the HLA molecule surface. The HLAMatchmaker and the PIRCHE-II (predicted indirectly recognizable HLA epitopes) algorithms are able to determine predictive epitope mismatches scores and de novo DSA (dnDSA) synthesis based on alloreactive eplets' identification. The aim of the present study was to assess, for the first time in liver transplantation, the complementarity between these two algorithms. We retrospectively analyzed a cohort of 407 adult and 133 pediatric liver transplant patients without preformed DSA, transplanted between 1991 and 2019 in Lyon and Montpellier. HLA antibodies were detected by single antigen bead assay. HLA typing of the donor-recipient pair was achieved by serological and/or DNA-based techniques. PIRCHE-II and HLAMatchmaker algorithms were then applied on both groups. During follow-up, 27.3% of adults and 38.3% of children developed dnDSA. HLA-DRB1 and DQB1-PIRCHE-II and HLAMatchmaker scores were significantly higher in dnDSA group compared to no DSA group for both pediatric and adult patients (except for PIRCHE-II HLA-DRB1 locus score in pediatrics). ROC curves allowed determining score thresholds classifying patients in low- and high-risk of dnDSA synthesis. The two algorithms' Kaplan-Meier curves showed a predicted incidence of dnDSA 20 years after transplantation significantly lower in the low-risk group compare with the high-risk group (log rank \textless0.05), in both cohorts, with a good negative predictive value. In conclusion, HLAMatchmaker and PIRCHE-II algorithms both are effective tools to identify anti-HLA immunization risk and to predict dnDSA formation after liver transplantation.

Alpha-1-antitrypsin deficiency (A1ATD) is a common genetic condition which predisposes to emphysema and liver disorders. It is estimated that 10-15% of homozygous individuals for the Z allele (PiZZ) may develop liver fibrosis. The optimal modalities to detect liver disease in PiZZ adult patients need to be defined. The aim of this prospective study was to perform a systematic non-invasive evaluation of the liver fibrosis by elastometry using FibroscanPatients followed in our respiratory unit were enrolled in this prospective study and underwent on the same day a physical examination, a biochemical profiling, an abdominal ultrasound (US) and a FibroscanTwenty-nine PiZZ adults (19 male) were included. Median age was 50.4 yrs (21.5-67.2). Median serum A1AT level was 0.20 g/L (0.15-0.33). Liver Function Tests (LFT) were not normal in 2 patients and US was abnormal in 6 patients. Two patients had both abdnormal LFT and US. FibroscanFibroscan