Publications by authors named "Olivier Boillot"

134 Publications

Liver Transplantation for Acute Intermittent Porphyria.

Liver Transpl 2020 Dec 1. Epub 2020 Dec 1.

Hepatology Division, Department of Upper GI Diseases, Porphyria Centre Sweden, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
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http://dx.doi.org/10.1002/lt.25959DOI Listing
December 2020

Determinants of short-term outcomes after pediatric liver transplantation: a single centre experience over 20 years.

Clin Res Hepatol Gastroenterol 2020 Nov 26:101565. Epub 2020 Nov 26.

Department of Digestive Diseases, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France; University Claude Bernard Lyon 1, Lyon, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinre.2020.10.009DOI Listing
November 2020

Long-term results of pediatric liver transplantation for autoimmune liver disease.

Clin Res Hepatol Gastroenterol 2020 Oct 17:101537. Epub 2020 Oct 17.

Université Claude Bernard Lyon 1, Lyon, France; Hospices Civils de Lyon, Hôpital Edouard Herriot, Femme-Mère-Enfant, Service d'Hépato-gastroentérologie, Lyon, France. Electronic address:

Background: 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.

Methods: Retrospective data from 30 children who underwent a first LT from 1988 to 2018 were collected.

Results: 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 LT<1year (p<0.0001), LT for fulminant failure (p=0.023) and LT for type 2 AIH (p=0.049) were significant predictive factors of death.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.clinre.2020.08.013DOI Listing
October 2020

Alcohol Consumption the Day of Liver Transplantation for Alcohol-Associated Liver Disease Does Not Affect Long-Term Survival: A Case-Control Study.

Liver Transpl 2021 01 19;27(1):34-42. Epub 2020 Dec 19.

Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, Montpellier, France.

Alcohol abstinence before liver transplantation (LT) for alcohol-associated liver disease (ALD) is required for every candidate. Some listed patients might relapse, resulting in LT for patients nonabstinent during the pretransplant period. Long-term survival outcomes of these patients have never been studied. We sought to determine whether alcohol consumption on the day of the LT influenced long-term survival after LT. We conducted a retrospective case-control study among French LT centers. Cases were defined as recipients between January 1995 and December 2007 having positive blood and/or urine alcohol levels the day of LT. Each case was paired with 2 controls corresponding to patients transplanted for ALD during the same trimester. Patients were classified into 3 categories per alcohol consumption: abstainers, occasional or transitory excessive consumers, or patients with a sustained excessive consumption (daily consumption >20-30 g/day). During the study period, 3052 LTs for ALD were conducted in France. We identified 42 cases paired with 84 controls. Median blood alcohol level was 0.4 g/L (range 0.1-4.1 g/L) and median urine alcohol level was 0.2 g/L (range 0.1-2.0 g/L). Median follow-up period until death or censoring was 12.9 years (CI = [12.3; 13.6]). Long-term survival was not different between the groups. Relapse to any alcohol consumption rate was higher in the case group (59.5%) than in the control group (38.1%, odds ratio 2.44; CI = [1.13; 5.27]), but sustained excessive consumption was not significantly different between the groups (33.3% versus 29.8% in case and control groups respectively, χ  = 0.68). Rates of recurrent cirrhosis and cirrhosis-related deaths were more frequent in the case group. Liver transplantation for nonabstinent patients during the immediate pretransplant period does not result in impaired long-term survival despite higher relapse and recurrent cirrhosis rates.
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http://dx.doi.org/10.1002/lt.25904DOI Listing
January 2021

Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry.

Liver Transpl 2020 11 12;26(11):1465-1476. Epub 2020 Oct 12.

Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France.

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 <60 mL/minute/1.73 m and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12 months after transplantation (mid-conversion) experienced improvement in eGFR (≥60 mL/minute/1.73 m ) at month 36. Only 20.9% and 17.4% among those converted beyond 12 months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60 mL/minute/1.73 m ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.
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http://dx.doi.org/10.1002/lt.25879DOI Listing
November 2020

Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis.

Liver Transpl 2020 11 22;26(11):1477-1491. Epub 2020 Oct 22.

Service d'Hépatologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), and its effect on the outcomes of liver transplantation (LT) for PSC is unclear. We retrospectively collected data from adults who underwent LT for PSC from 1989 to January 2018 in 4 French LT centers. We compared the rates of patient and graft survivals and of complications after LT. Among 87 patients, 52 (60%) had preexisting IBD. Excluding those who died within the first 3 months, the 10-year patient survival and graft survival rates were 92.6% (95% confidence interval [CI], 84.3%-100%) and 77.1% (53.8%-85.3%), respectively, in the PSC with IBD (PSC-IBD) group and 97.1% (91.4%-100%; P = 0.44) and 83.2% (69.6%-96.9%; P = 0.43) in the isolated PSC group, respectively. Exposure to azathioprine after LT was significantly associated with mortality (odds ratio [OR], 15.55; 1.31-184.0; P = 0.03), whereas exposure to mycophenolate mofetil was associated with improved survival (OR, 0.17; 95% CI, 0.04-0.82; P = 0.03), possibly an era effect. The rate of recurrent PSC was 21% in the PSC-IBD group and 11% in the isolated PSC group (P = 0.24). Severe infections occurred in 125 per 1000 person-years in both groups. Exposure to mycophenolate mofetil was associated with a lower risk of infection (OR, 0.26; 95% CI, 0.08-0.85; P = 0.03). The presence of IBD was associated with cytomegalovirus (CMV) infection (OR, 3.24; 95% CI, 1.05-9.98; P = 0.04). IBD prior to LT for PSC may not affect patient or transplant survival but may increase the risk of CMV infection.
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http://dx.doi.org/10.1002/lt.25838DOI Listing
November 2020

Real life experience of mycophenolate mofetil monotherapy in liver transplant patients.

Clin Res Hepatol Gastroenterol 2021 Jan 11;45(1):101451. Epub 2020 Jun 11.

Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France. Electronic address:

Background: Mycophenolate mofetil (MMF) monotherapy following liver transplantation (LT) remains controversial due to a risk of acute rejection. The aim of this study was to report the largest multicenter experience of the use a MMF monotherapy guided by therapeutic drug monitoring using pharmacoslope modeling and Bayesian estimations of the MPA inter-dose AUC (AUC) before withdrawing calcineurin inhibitors (CNI) and to evaluate the benefit of MMF monotherapy.

Methods: MMF daily doses were adjusted to reach the AUC target of 45μg.h/mL. Then CNI were withdrawn and patients were followed on liver test and clinical outcomes.

Main Findings: From 2000-2014, in 2 transplantation centers, 94 liver transplant recipients received MMF monotherapy 6.5±4 years after LT. The mean AUC was 45.5±16μg.h/mL. During follow-up, 4 patients experienced acute rejection (4%). During the first year, estimated glomerular filtration rate (eGFR) improved from 46.2±10.5 to 49.1±11.5mL/kg/min (P=0.025). Benefit persisted at year 5. In patients with metabolic syndrome, eGFR did not improve.

Conclusion: MMF monotherapy regimen appears usually safe and beneficial, with low risk of acute rejection and eGFR improvement. Therapeutic drug monitoring strategy seemed useful by identifying 14% of patients with low MMF exposure.
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http://dx.doi.org/10.1016/j.clinre.2020.04.017DOI Listing
January 2021

Predictive value of HLAMatchmaker and PIRCHE-II scores for de novo donor-specific antibody formation after adult and pediatric liver transplantation.

Transpl Immunol 2020 08 16;61:101306. Epub 2020 May 16.

CHU Saint Eloi, Département d'hépatologie et transplantation hépatique, Montpellier, France. Electronic address:

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 <0.05), 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.
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http://dx.doi.org/10.1016/j.trim.2020.101306DOI Listing
August 2020

Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.

J Hepatol 2020 Sep 7;73(3):559-565. Epub 2020 Apr 7.

Transplant Hepatology Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Claude Bernard University, Lyon, France.

Background & Aims: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT.

Methods: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983-2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10-15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models.

Results: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28-0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13-0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22-0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49-0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28-3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death.

Conclusions: Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality.

Lay Summary: Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We performed the largest international study of transplanted patients with primary biliary cholangitis to date. Preventive administration of ursodeoxycholic acid after liver transplantation was associated with reduced risk of disease recurrence, graft loss, liver-related and all-cause mortality. A regimen combining cyclosporine and preventive ursodeoxycholic acid was associated with the best outcomes.
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http://dx.doi.org/10.1016/j.jhep.2020.03.043DOI Listing
September 2020

Outcome of Liver Transplant Patients With Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibodies.

Liver Transpl 2020 02 28;26(2):256-267. Epub 2019 Nov 28.

Université Claude Bernard Lyon 1, Villeurbanne, France.

After liver transplantation (LT), the role of preformed donor-specific anti-human leukocyte antigen antibodies (pDSAs) remains incompletely understood. We conducted a retrospective, case-control analysis to determine the impact of pDSAs after LT in 3 French transplant centers (Bordeaux, Lyon, and Toulouse). Among the 1788 LTs performed during the study period, 142 (7.9%) had at least 1 pDSA. The patient survival rate was not different between patients who received an LT with pDSAs and the matched-control group. A liver biopsy was performed 1 year after transplantation in 87 recipients. The metavir fibrosis score did not differ between both groups (1 ± 0.8 versus 0 ± 0.8; P = 0.80). However, undergoing a retransplantation (hazard ratio [HR] = 2.6, 95% confidence interval [CI], 1.02-6.77; P = 0.05) and receiving induction therapy with polyclonal antibodies (HR = 2.5; 95% CI, 1.33-4.74; P = 0.01) were associated with a higher risk of mortality. Nonetheless, high mean fluorescence intensity (MFI) donor-specific antibodies (ie, >10,000 with One Lambda assay or >5000 with Immucor assay) were associated with an increased risk of acute rejection (HR = 2.0; 95% CI, 1.12-3.49; P = 0.02). Acute antibody-mediated rejection was diagnosed in 10 patients: 8 recipients were alive 34 (1-125) months after rejection. The use of polyclonal antibodies or rituximab as an induction therapy did not reduce the risk of acute rejection, but it increased the risk of infectious complications. In conclusion, high MFI pDSAs increase the risk of graft rejection after LT, but they do not reduce medium-term and longterm patient survival. The use of a T or B cell-depleting agent did not reduce the risk of acute rejection.
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http://dx.doi.org/10.1002/lt.25663DOI Listing
February 2020

Natural History of Recurrent Alcohol-Related Cirrhosis After Liver Transplantation: Fast and Furious.

Liver Transpl 2020 01 22;26(1):25-33. Epub 2019 Nov 22.

Fédération des Spécialités Digestives, Hôpital Édouard Herriot, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

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.
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http://dx.doi.org/10.1002/lt.25647DOI Listing
January 2020

Anastomotic bilio-biliary stricture after adult liver transplantation: A retrospective study over 20 years in a single center.

Clin Res Hepatol Gastroenterol 2020 09 20;44(4):564-571. Epub 2019 Sep 20.

Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.

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.
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http://dx.doi.org/10.1016/j.clinre.2019.08.008DOI Listing
September 2020

Tacrolimus exposure after liver transplantation for alcohol-related liver disease: Impact on complications.

Transpl Immunol 2019 10 24;56:101227. Epub 2019 Jul 24.

Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Background: Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.

Objective: The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.

Methods: All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.

Results: The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.

Conclusion: Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.
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http://dx.doi.org/10.1016/j.trim.2019.101227DOI Listing
October 2019

Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis.

Hepatology 2019 10 31;70(4):1392-1408. Epub 2019 May 31.

BCI Laboratory, Université Grenoble Alpes, Inserm, CEA, Grenoble, France.

Bone morphogenetic protein 9 (BMP9) is a circulating factor produced by hepatic stellate cells that plays a critical role in vascular quiescence through its endothelial receptor activin receptor-like kinase 1 (ALK1). Mutations in the gene encoding ALK1 cause hereditary hemorrhagic telangiectasia type 2, a rare genetic disease presenting hepatic vessel malformations. Variations of both the circulating levels and the hepatic mRNA levels of BMP9 have been recently associated with various forms of hepatic fibrosis. However, the molecular mechanism that links BMP9 with liver diseases is still unknown. Here, we report that Bmp9 gene deletion in 129/Ola mice triggers hepatic perisinusoidal fibrosis that was detectable from 15 weeks of age. An inflammatory response appeared within the same time frame as fibrosis, whereas sinusoidal vessel dilation developed later on. Proteomic and mRNA analyses of primary liver sinusoidal endothelial cells (LSECs) both revealed that the expression of the LSEC-specifying transcription factor GATA-binding protein 4 was strongly reduced in Bmp9 gene knockout (Bmp9-KO) mice as compared with wild-type mice. LSECs from Bmp9-KO mice also lost the expression of several terminal differentiation markers (Lyve1, Stab1, Stab2, Ehd3, Cd209b, eNos, Maf, Plvap). They gained CD34 expression and deposited a basal lamina, indicating that they were capillarized. Another main characteristic of differentiated LSECs is the presence of permeable fenestrae. LSECs from Bmp9-KO mice had a significantly reduced number of fenestrae. This was already observable in 2-week-old pups. Moreover, we could show that addition of BMP9 to primary cultures of LSECs prevented the loss of their fenestrae and maintained the expression levels of Gata4 and Plvap. Conclusion: Taken together, our observations show that BMP9 is a key paracrine regulator of liver homeostasis, controlling LSEC fenestration and protecting against perivascular hepatic fibrosis.
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http://dx.doi.org/10.1002/hep.30655DOI Listing
October 2019

Pregnancy and donor-specific HLA-antibody-mediated rejection after liver transplantation: "Liaisons dangereuses"?

Transpl Immunol 2019 06 8;54:47-51. Epub 2019 Feb 8.

Etablissement Français du Sang, Lyon, France.

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.
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http://dx.doi.org/10.1016/j.trim.2019.02.002DOI Listing
June 2019

Portal vein thrombosis and liver cirrhosis: Long-term anticoagulation is effective and safe.

Clin Res Hepatol Gastroenterol 2019 08 18;43(4):395-402. Epub 2018 Dec 18.

Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyn, 69437 Lyon, France; Université Claude-Bernard Lyon 1, 69008 Lyon, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinre.2018.11.011DOI Listing
August 2019

Recurrence of Hereditary Hemorrhagic Telangiectasia After Liver Transplantation: Clinical Implications and Physiopathological Insights.

Hepatology 2019 05 7;69(5):2232-2240. Epub 2019 Mar 7.

Département de Biologie et Pathologie Médicales, Service de Pathologie Moléculaire, Gustave Roussy Cancer Campus, Villejuif, France.

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.
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http://dx.doi.org/10.1002/hep.30424DOI Listing
May 2019

mTOR inhibitors in pediatric liver transplant recipients.

Clin Res Hepatol Gastroenterol 2019 08 6;43(4):403-409. Epub 2018 Dec 6.

Swiss center for liver disease in children, university hospitals Geneva, 1205 Geneva, Switzerland.

Background: During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients.

Methods: All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed.

Results: The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 μg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function.

Conclusion: Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.
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http://dx.doi.org/10.1016/j.clinre.2018.11.010DOI Listing
August 2019

Class II Human Leukocyte Antigen Epitope Mismatch Predicts De Novo Donor-Specific Antibody Formation After Liver Transplantation.

Liver Transpl 2019 01;25(1):184-185

Hospices Civils de Lyon Hôpital Edouard Herriot Unité de Transplantation Hépatique, Lyon, France.

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http://dx.doi.org/10.1002/lt.25357DOI Listing
January 2019

De Novo Malignancies Screening After Liver Transplantation for Alcoholic Liver Disease: A Comparative Opportunistic Study.

Liver Transpl 2018 12;24(12):1690-1698

Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

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.
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http://dx.doi.org/10.1002/lt.25336DOI Listing
December 2018

Total donor chimerism with bone marrow GVHD after multivisceral transplantation.

Am J Hematol 2018 11 9;93(11):E372-E374. Epub 2018 Sep 9.

Department of Hematology, Centre Léon Bérard, Lyon, France.

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http://dx.doi.org/10.1002/ajh.25253DOI Listing
November 2018

Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients.

Liver Transpl 2018 10;24(10):1425-1436

Unité de Transplantation Hépatique, et Université Claude Bernard Lyon 1, Hôpital Edouard Herriot, Lyon, France.

De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomédecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08-2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09-2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68-3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97-9.48), esophageal (SIR = 4.76; 95% CI, 3.56-6.24), lung (SIR = 2.56; 95% CI, 2.21-2.95), and lip-mouth-pharynx (SIR = 2.20; 95% CI, 1.72-2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT.
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http://dx.doi.org/10.1002/lt.25310DOI Listing
October 2018

Immunosuppressive regimen and risk for de novo malignancies after liver transplantation for alcoholic liver disease.

Clin Res Hepatol Gastroenterol 2018 10 31;42(5):427-435. Epub 2018 May 31.

Fédération des spécialités digestives, hôpital Edouard-Herriot, hospices civils de Lyon, 69437 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69437 Lyon cedex 03, France.

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)).

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.
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http://dx.doi.org/10.1016/j.clinre.2018.04.011DOI Listing
October 2018

Prevalence, Risk Factors, and Impact of Donor-Specific Alloantibodies After Adult Liver Transplantation.

Liver Transpl 2018 08;24(8):1091-1100

Unité de Transplantation Hépatique, Hospices Civils de Lyon, Lyon, France.

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.
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http://dx.doi.org/10.1002/lt.25177DOI Listing
August 2018

Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients.

J Am Acad Dermatol 2018 Jul 4;79(1):84-91. Epub 2018 Jan 4.

Department of Digestive Diseases, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Background: Nonmelanoma skin cancers (NMSCs) are the most frequent cancers in solid organ transplant recipients, with a high rate of subsequent tumors.

Objectives: To describe subsequent NMSCs in a large cohort of liver transplant recipients (LTRs) with long follow-up and analyze the factors influencing it, including immunosuppressive regimen.

Methods: A total of 96 LTRs (76 male) with a personal post-transplant history of squamous cell carcinoma, basal cell carcinoma or Bowen's disease were included, with a median follow-up of 12.4 years (range, 1.5-27.8) after liver transplantation.

Results: The median follow-up after first NMSC was 6.4 years (range, 0.17-22.1). In all, 52 patients (53.1%) developed 141 subsequent NMSCs with a basal cell carcinoma-to-squamous cell carcinoma ratio of 1.8:1. The actuarial risk for development of a second NMSC was 13.7% at 1 year, 28.4% at 2 years, 49.4% at 5 years, 65.7% at 10 years, and 88.4% at 15 years. Multivariate analysis found that skin phototype I or II (vs III or IV) was a significant risk factor for development of a second NMSC (hazard ratio, 2.556; 95% confidence interval, 1.45-4.48; P = .001), whereas withdrawal of calcineurin inhibitors was significantly protective (hazard ratio, 0.358; 95% confidence interval, 0.142-0.902; P = .029).

Limitations: Retrospective analysis.

Conclusions: Subsequent NMSCs are very frequent in LTRs, and conversion from a calcineurin inhibitor-based immunosuppressive regimen to a mammalian target of rapamycin inhibitor/antimetabolite-based immunosuppressive regimen can reduce subsequent NMSCs.
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http://dx.doi.org/10.1016/j.jaad.2017.12.063DOI Listing
July 2018

Deleterious impact of C3d-binding donor-specific anti-HLA antibodies after pediatric liver transplantation.

Transpl Immunol 2017 12 3;45:8-14. Epub 2017 Aug 3.

Unité de Transplantation hépatique, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

Background: 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.

Methods: 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.

Results: 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 and >15years 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 (p<0.01) 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).

Conclusion: 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.
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http://dx.doi.org/10.1016/j.trim.2017.08.001DOI Listing
December 2017

Portal Vein Thrombosis and Nephrotic Syndrome After Liver Transplant.

Exp Clin Transplant 2019 06 5;17(3):418-420. Epub 2017 Jun 5.

From the Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation Hépatique, and the Université Claude Bernard Lyon.

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.
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http://dx.doi.org/10.6002/ect.2016.0259DOI Listing
June 2019

Survival and prognostic factors after adjuvant iodine-labeled lipiodol for hepatocellular carcinoma: a retrospective analysis of 106 patients over 20 years.

Ann Nucl Med 2017 Jun 24;31(5):379-389. Epub 2017 Mar 24.

Hospices civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, pavillon L, 69437, Lyon Cedex 03, France.

Objective: 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 I-lipiodol after curative treatment of HCC in terms of recurrence and survival in a large cohort of patients with a long follow-up.

Methods: All patients treated with I-lipiodol after curative treatment of HCC in two French centers from 1991 to 2009 were included in a retrospective cohort study.

Results: 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].

Conclusion: Our results suggest that the effect of I-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.
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http://dx.doi.org/10.1007/s12149-017-1165-4DOI Listing
June 2017

Prognostic Value of Metabolic Liver Function Tests: a Study on 711 Cirrhotic Patients.

J Gastrointestin Liver Dis 2016 Sep;25(3):337-43

Department of Digestive Diseases, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France

Background And Aims: The prognosis of cirrhotic patients is usually assessed by Child-Pugh and MELD scores. Metabolic liver function tests such as aminopyrine breath test (ABT) and indocyanine green clearance (IGC) have been shown to reveal hepatocellular dysfunction. The aim of this retrospective study was to compare the prognostic value of the MELD score, Child-Pugh score, ABT and IGC in a large cohort of cirrhotic patients.

Methods: Between January 1996 and June 2008, 711 cirrhotic patients were included and the primary endpoint was survival without LT. The ROC curves with c-statistics, correlation coefficient and survival were calculated.

Results: Metabolic function tests and scores were strongly correlated. At the time of evaluation, 111 patients had died and 520 had received a transplant. Prognostic ability (estimated by the AUROC curve) to predict survival without LT at 6 months was 0.662, 0.691, 0.738 and 0.715 for ABT, IGC, Child-Pugh score and MELD score, respectively. Similarly, at 1 year, AUROC was 0.738 for Child-Pugh score, 0.716 for MELD score, 0.693 for IGC clearance and 0.651 for ABT.

Conclusions: Our results strongly confirm that IGC and ABT have a high prognostic value in cirrhotic patients, similar to Child-Pugh and MELD scores. They could be developed to routinely evaluate the prognosis of patients in addition to clinical and biochemical data.
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http://dx.doi.org/10.15403/jgld.2014.1121.253.lftDOI Listing
September 2016

Living or Brain-dead Donor Liver Transplantation for Hepatocellular Carcinoma: A Multicenter, Western, Intent-to-treat Cohort Study.

Ann Surg 2017 12;266(6):1035-1044

*Service de Chirurgie Hépato-Bilio-Pancréatique, AP-HP Hôpital Henri Mondor, Créteil, France †Service de Santé Publique, AP-HP Hôpital Henri Mondor, Université Paris- Est Créteil, Créteil, France ‡Service de Chirurgie Hépato-Bilio-Pancréatique, AP-HP Hôpital Paul Brousse, Villejuif, France §Service de Chirurgie Hépato-Bilio-Pancréatique, AP-HP Hôpital Beaujon, Clichy, France ¶Service de Chirurgie Hépato-Bilio-Pancréatique, Hôpital Edouard Herriot, Lyon, France ||Service de Chirurgie Hépato-Bilio-Pancréatique, AP-HP Hôpital Saint Antoine, Paris, France **Service de Radiologie, AP-HP Hôpital Henri Mondor, Créteil, France ††Service d'Hépatologie, Hôpital Henri Mondor, Créteil, France.

Objective: An intent-to-treat analysis of overall survival (ITT-OS) of cirrhotic patients with hepatocellular carcinoma (HCC) listed for living donor liver transplantation (LDLT) or brain-dead donor liver transplantation (BDLT) across 5 French liver transplant (LT) centers.

Background: Comparisons of HCC outcomes after LDLT and BDLT measured from time of transplantation have yielded conflicting results.

Methods: Records from 861 cirrhotic patients with HCC consecutively listed for either LDLT (n = 79) or BDLT (n = 782) from 2000 to 2009 were analyzed for ITT-OS using a Cox model; and tumor recurrence using 2 competitive risk models.

Results: Tumor staging was similar between groups. In total, 162 patients dropped out (20.7%), all from Group BDLT (P < 0.0001). The postoperative mortality rate and the retransplantation rate were similar between LDLT and BDLT. At 5 years, no statistically significant difference was found in ITT-OS between LDLT and BDLT groups (73.2% vs 66.7%; P = 0.062). LDLT waitlist inclusion (hazard ratio: 0.61 (0.39-0.96); P = 0.034) and a time-of-listing MELD score ≥ 25 (hazard ratio: 1.93 (1.15-3.26); P = 0.014) were independent predictors of ITT-OS. Similar 5-year post-LT OS rates (73.2% and 73.0% for Group LDLT and Group BDLT, respectively; P = 0.407) and HCC recurrence rates (10.9% and 11.2% for Group LDLT and Group BDLT, respectively; P = 0.753) were found. Upon explant analysis, tumors exceeding the Milan criteria, macroscopic vascular invasion, and AFP score>2 were independent predictors of recurrence, whereas LT type was not.

Conclusions: LDLT improves ITT-OS, and it is not a risk factor for tumor recurrence. Therefore, LDLT and BDLT should be equally encouraged in countries where both are available.
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http://dx.doi.org/10.1097/SLA.0000000000001986DOI Listing
December 2017