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

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.

Safe and effective digestive endoscopic resection in patients with cirrhosis: a single-center experience.

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 < 0.01), antiplatelet medication (P = 0.02), and lower glomerular filtration rate (GFR) (P = 0.01) in univariate analysis. Duodenal location and lower GFR remained statistically significant in multivariate analysis, with respective odds ratios for bleeding of 52.12 and 1.04. No liver decompensation occurred after endoscopic resection. 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.

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

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.

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

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.

Colon capsule versus computed tomography colonography for colorectal cancer screening in patients with positive fecal occult blood test who refuse colonoscopy: a randomized trial.

OBJECTIVE: Some patients (10 % - 32 %) with a positive guaiac fecal occult blood test (gFOBT) do not undergo the recommended colonoscopy. The aim of this study was to compare video capsule endoscopy (VCE) and computed tomography colonography (CTC) in terms of participation rate and detection outcomes when offered to patients with a positive gFOBT who did not undergo the recommended colonoscopy. METHODS: An invitation letter offering CTC or VCE was sent to selected patients after randomization. Acceptance of the proposed (or alternative) procedure and procedure results were recorded. Sample size was evaluated according to the hypothesis of a 13 % increase of participation with VCE. RESULTS: A total of 756 patients were targeted. Following the invitation letter, 5.0 % (19/378) of patients underwent the proposed VCE and 7.4 % (28/378) underwent CTC, (P = 0.18). Following the letter, 9.8 % (37/378) of patients in the VCE group underwent a diagnostic procedure (19 VCE, 1 CTC, 17 colonoscopy) vs. 10.8 % in the CTC group (41/378: 28 CTC, 13 colonoscopy; P = 0.55). There were more potentially neoplastic lesions diagnosed in the VCE group than in the CTC group (12/20 [60.0 %] vs. 8/28 [28.6 %]; P = 0.04). Thus, 15/20 noninvasive procedures in the VCE group (19 VCE, 1 CTC; 75.0 %) vs. 10/28 in the CTC group (35.7 %; P = 0.01) resulted in a recommendation of further colonoscopy, but only 10/25 patients actually underwent this proposed colonoscopy. CONCLUSION: Patients with a positive gFOBT result who do not undergo the recommended colonoscopy are difficult to recruit to the screening program and simply proposing an additional, less-invasive procedure, such as VCE or CTC, is not an effective strategy.ClinicalTrials.govNCT02558881TRIAL REGISTRATION: Randomized, controlled trial NCT02558881 at clinicaltrials.gov.

Adenoma detection with blue-water infusion colonoscopy: a randomized trial.

Background and aims Colonoscopy is currently the reference method to detect colorectal neoplasia, yet some adenomas remain undetected. The water infusion technique and dying with indigo carmine has shown interesting results for reducing this miss rate. The aim of this study was to compare the adenoma detection rate (adenoma and adenocarcinoma; ADR) and the mean number of adenomas per patient (MAP) for blue-water infusion colonoscopy (BWIC) versus standard colonoscopy. Methods We performed a multicenter, randomized controlled trial in eight units, including patients with a validated indication for colonoscopy (symptoms, familial or personal history, fecal occult blood test positive). Consenting patients were randomized 1:1 to BWIC or standard colonoscopy. All colonoscopies were performed by experienced colonoscopists. All colonoscopy quality indicators were prospectively recorded. Results Among the 1065 patients included, colonoscopies were performed completely for 983 patients (514 men; mean age 59.1). The ADR was not significantly different between the groups; 40.4 % in the BWIC group versus 37.5 % in the standard colonoscopy group (odds ratio [OR] 1.13; 95 % confidence interval [CI] 0.87 - 1.48; P = 0.35). MAP was significantly greater in the BWIC group (0.79) than in the standard colonoscopy group (0.64; P = 0.005). For advanced adenomas, the results were 50 (10.2 %) and 36 (7.3 %), respectively (P = 0.10). The cecal intubation rate was not different but the time to cecal intubation was significantly longer in BWIC group (9.9 versus 6.2 minutes; P < 0.001). Conclusion Despite the higher MAP with BWIC, the routine use of BWIC does not translate to a higher ADR. Whether increased detection ultimately results in a lower rate of interval carcinoma is not yet known. CLINICAL TRIALS REGISTRATION: EudraCT 2012-A00548 - 35; NCT01937429.

Severe alcoholic relapse after liver transplantation: What consequences on the graft? A study based on liver biopsies analysis.

Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT), but up to 20% of patients experience severe alcoholic relapse. The aims of this study were to evaluate the impact of severe alcoholic relapse on the graft (based on histological examination) and to identify predictive factors associated with recurrent alcoholic cirrhosis (RAC). From 1990 to 2010, 369 patients underwent LT for ALD at Edouard Herriot Hospital (Lyon, France) and survived more than 1 year. All patients who presented severe alcoholic relapse and histological follow-up were included. Liver biopsies were performed at 1 and 5 years and at every 5 years after LT, and when clinically indicated. The median follow-up after LT was 11 years (range, 3-18 years). Severe alcoholic relapse was observed in 73 (20%) of the 369 patients, from whom 56 patients with histological evaluation were included. RAC was diagnosed in 18 (32%) of the 56 patients included, which represents 5% of the 369 patients transplanted for ALD. The median delay between LT and RAC was 6 years (range, 3-10 years) and 4.5 years (range, 2-8 years) after severe alcoholic relapse. The median cumulated years of alcohol use before RAC was 3.5 years (range, 2-7 years). The cumulative risk for F4 fibrosis was 15% at 3 years, 32% at 5 years, and 54% at 10 years after severe alcoholic relapse. A young age at LT (≤50 years old) and an early onset of heavy drinking (within the first 3 years after LT) were associated with RAC. In conclusion, severe alcoholic relapse usually occurs in the first years after LT and is responsible for accelerated severe graft injury. Liver Transplantation 22 773-784 2016 AASLD.

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

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.

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

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.

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

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 ±â€¯7.3 years, and followed during 11.6 ±â€¯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.

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

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.

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

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.

Methylprednisolone liver toxicity: A new case and a French regional pharmacovigilance survey.

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.