Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study.

BACKGROUND & AIMS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes. METHODS: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared. RESULTS: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22). CONCLUSION: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup. IMPACTS AND IMPLICATIONS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup.

Autoimmune hepatitis recurrence after liver transplantation: "Les jeux sont faits".

Autoimmune hepatitis (AIH) may recur after liver transplantation (LT). The aims of this study were to evaluate the incidence and risk factors for recurrent autoimmune hepatitis (rAIH). A multicenter retrospective French nationwide study, including all patients aged ≥16 transplanted for AIH, with at least 1 liver biopsy 1 year after LT, was conducted between 1985 and 2018. Risk factors for rAIH were identified using a multivariate Cox regression model. Three hundred and forty-four patients were included (78.8% women) with a median age at LT of 43.6 years. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1-93.2). Actuarial risk for developing rAIH was 41.3% 20 years after LT. In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R- mismatch status (HR=2.0; 95% CI: 1.1-3.6; p =0.03), followed by associated autoimmune condition. Twenty-one patients (27.6% of rAIH patients) developed liver graft cirrhosis after rAIH. Independent risk factors for these severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. Recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Conventional cytotoxic chemotherapy for gastrointestinal cancer in patients with cirrhosis: A multicentre case-control study.

BACKGROUND & AIMS: Progresses in management make a higher proportion of cirrhotic patients with gastrointestinal (GI) cancer candidates to chemotherapy. Data are needed on the safety and liver-related events associated with the use of chemotherapy in these patients. METHODS: Forty-nine patients with cirrhosis receiving chemotherapy against GI cancer from 2013 to 2018 were identified in the French Health Insurance Database using ICD-10 codes K70-K74, and matched 1:2 to non-cirrhotic controls (n = 98) on age, tumour type and type of treatment. Adverse events (AE), dose tapering, discontinuation rate, liver-related events and survival rate were compared. RESULTS: Patients with cirrhosis (Child-Pugh A 91%) more often received lower doses (38.8% vs 7.1%, p < .001), without significant differences in terms of grade 3/4 AE or dose tapering rates (29.6% vs. 36.7%; 22.3% vs 24.4%, respectively). Treatment discontinuation rate was higher in patients with cirrhosis (23.3% vs. 11.3%, p = .005). Child-Pugh (p = .007) and MELD (p = .025) scores increased under chemotherapy. Five patients with cirrhosis (10.2%) had liver decompensation within 12 months, and 17.2% of deaths in the cirrhosis group were liver-related versus 0% in matched controls. WHO-PS stage > 1 (HR 3.74, CI95%: 2.13-6.57, p < .001), TNM-stage M1 (HR 3.61, CI 95%: 1.82-7.16, p < .001), non-colorectal cancer (HR 1.73, CI 95%: 1.05-2.86, p = .032) and bilirubin higher than 5 mg/dL (HR 2.26, CI 95%: 1.39-3.70, p < .001) were independent prognostic factors of 2-year mortality, whereas cirrhosis was not. CONCLUSIONS: Chemotherapy should be proposed only in patients with compensated cirrhosis with close monitoring of liver function. Dose management remains challenging. Multidisciplinary management is warranted to improve these patients' outcomes.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

French guidelines on TIPS: Indications and modalities.

Transjugular intrahepatic portosystemic shunt (TIPS) has become essential in the treatment or prevention of portal hypertension-related complications. In the early 1990s, the primary indication was refractory bleeding. It is now proposed for the treatment of ascites for the prevention of bleeding and in patients with vascular diseases of the liver. Thus, there are a growing number of patients being treated with TIPS all over the world. The broadening of indications, the involvement of multiple stakeholders, the need for an accurate selection, the positioning in relation to transplantation and the lack of standardization in pre-therapeutic assessment, in the procedure itself and in the follow-up have led the board of the French Association for the Study of the Liver to establish recommendations.

Treatment of donor-specific anti-HLA antibodies-mediated rejection after liver transplantation: A French nationwide retrospective study.

The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases.

Liver transplantation for autoimmune hepatitis: Pre-transplant does not predict the early post-transplant outcome.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare indication (<5%) for liver transplantation (LT). The aim of this study was to describe the early outcome after LT for AIH. METHODS: A multicenter retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Occurrences of biliary and vascular complications, rejection, sepsis, retransplantation and death were collected during the first year after LT. RESULTS: A total of 344 patients (78.8% of women, 17.0% of (sub)fulminant hepatitis and 19.2% of chronic liver diseases transplanted in the context of acute-on-chronic liver failure [ACLF]) were included, with a median age at LT of 43.6 years. Acute rejection, sepsis, biliary and vascular complications occurred in respectively 23.5%, 44.2%, 25.3% and 17.4% of patients during the first year after LT. One-year graft and patient survivals were 84.3% and 88.0% respectively. The main cause of early death was sepsis. Pre-LT immunosuppression was not associated with an increased risk for early infections or surgical complications. Significant risk factors for septic events were LT in the context of (sub)fulminant hepatitis or ACLF, acute kidney injury at the time of LT (AKI) and occurrence of biliary complications after LT. AKI was the only independent factor associated with graft (HR = 2.5; 95% CI: 1.1-5.4; p = .02) and patient survivals (HR = 2.6; 95% CI: 1.0-6.5; p = .04). CONCLUSION: Early prognosis is good after LT for AIH and is not impacted by pre-LT immunosuppression but by the presence of AKI at the time of LT.

Long-term outcome of liver transplantation for autoimmune hepatitis: A French nationwide study over 30 years.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). The aims of this study were to evaluate long-term survival after LT for AIH and prognostic factors, especially the impact of recurrent AIH (rAIH). METHODS: A multicentre retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Early deaths and retransplantations (≤6 months) were excluded. RESULTS: The study population consisted of 301 patients transplanted from 1987 to 2018. Median age at LT was 43 years (IQR, 29.4-53.8). Median follow-up was 87.0 months (IQR, 43.5-168.0). Seventy-four patients (24.6%) developed rAIH. Graft survival was 91%, 79%, 65% at 1, 10 and 20 years respectively. Patient survival was 94%, 84% and 74% at 1, 10 and 20 years respectively. From multivariate Cox regression, factors significantly associated with poorer patient survival were patient age ≥58 years (HR = 2.9; 95% CI, 1.4-6.2; p = 0.005) and occurrence of an infectious episode within the first year after LT (HR = 2.5; 95% CI, 1.2-5.1; p = 0.018). Risk factors for impaired graft survival were: occurrence of rAIH (HR = 2.7; 95% CI, 1.5-5.0; p = 0.001), chronic rejection (HR = 2.9; 95% CI, 1.4-6.1; p = 0.005), biliary (HR = 2.0; 95% CI, 1.2-3.4; p = 0.009), vascular (HR = 1.8; 95% CI, 1.0-3.1; p = 0.044) and early septic (HR = 2.1; 95% CI, 1.2-3.5; p = 0.006) complications. CONCLUSION: Our results confirm that survival after LT for AIH is excellent. Disease recurrence and chronic rejection reduce graft survival. The occurrence of an infectious complication during the first year post-LT identifies at-risk patients for graft loss and death.

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC0-24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC0-24 h (V4). AUC0-24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC0-24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

Multicenter study on recent portal venous system thrombosis associated with cytomegalovirus disease.

BACKGROUND & AIMS: Recent non-malignant non-cirrhotic portal venous system thrombosis (PVT) is a rare condition. Among risk factors for PVT, cytomegalovirus (CMV) disease is usually listed based on a small number of reported cases. The aim of this study was to determine the characteristics and outcomes of PVT associated with CMV disease. METHODS: We conducted a French multicenter retrospective study comparing patients with recent PVT and CMV disease ("CMV positive"; n = 23) to patients with recent PVT for whom CMV testing was negative ("CMV negative"; n = 53) or unavailable ("CMV unknown"; n = 297). RESULTS: Compared to patients from the "CMV negative" and "CMV unknown" groups, patients from the "CMV positive" group were younger, more frequently had fever, and had higher heart rate, lymphocyte count and serum ALT levels (p ≤0.01 for all). The prevalence of immunosuppression did not differ between the 3 groups (4%, 4% and 6%, respectively). Extension of PVT was similar between the 3 groups. Thirteen out of 23 "CMV positive" patients had another risk factor for thrombosis. Besides CMV disease, the number of risk factors for thrombosis was similar between the 3 groups. Heterozygosity for the prothrombin G20210A gene variant was more frequent in "CMV positive" patients (22%) than in the "CMV negative" (4%, p = 0.01) and "CMV unknown" (8%, p = 0.03) groups. Recanalization rate was not influenced by CMV status. CONCLUSIONS: In patients with recent PVT, features of mononucleosis syndrome should raise suspicion of CMV disease. CMV disease does not influence thrombosis extension nor recanalization. More than half of "CMV positive" patients have another risk factor for thrombosis, with a particular link to the prothrombin G20210A gene variant. LAY SUMMARY: Patients with cytomegalovirus (CMV)-associated portal venous system thrombosis have similar thrombosis extension and evolution as patients without CMV disease. However, patients with CMV-associated portal venous system thrombosis more frequently have the prothrombin G20210A gene variant, suggesting that these entities act synergistically to promote thrombosis.

Lung Infection Affects Access to Treatment and Short-Term Outcome in Patients With Severe Alcohol-Related Hepatitis Treated With Corticosteroids.

INTRODUCTION: Severe alcohol-related hepatitis (AH) is associated with an increased risk of infection, but the impact of pneumonia has not been specifically analyzed in a specific cohort. METHODS: All patients admitted for severe AH between 2002 and 2020 were prospectively included. Systematic screening for infection was performed at admission and renewed in the case of clinical suspicion. RESULTS: We included 614 patients (60.4% men, mean age 49.9 years, median model for end-stage liver disease [MELD] 25.2, bilirubin 18.1 mg/dL), 202 (32.9%) with infections at admission (73 lung infections). Encephalopathy ( P = 0.006), MELD score ( P = 0.0002), and tobacco exposure (past vs never smokers: P = 0.002 or active vs past smokers: P = 0.005) were associated with lung infection at admission on multivariate analysis. Factors independently associated with death before steroid initiation were encephalopathy ( P = 0.003), MELD score ( P = 0.05), and especially lung infection ( P < 0.0001). Thus, patients with a lung infection had a lower probability of receiving steroids than those with other infections and noninfected patients: 54.8 vs 88.4 vs 98.1% ( P < 0.0001). One hundred forty-six of the 558 patients who received corticosteroids developed infection, including 57 (39.04%) pneumonias. The risk of respiratory and nonrespiratory infection was higher in nonresponders to steroids (Lille score ≥0.45) than in responders: 13% vs 7.6%, P = 0.03 and 27.9% vs 10.6%, P < 0.001, respectively. The variables independently associated with 3-month mortality after steroid initiation were lung infection ( P = 0.004), nonresponse to steroids ( P < 0.0001), MELD score ( P = 0.0003), ascites ( P = 0.003), and encephalopathy ( P = 0.018), whereas nonrespiratory infections were not ( P = 0.91). DISCUSSION: Lung infection is frequent during severe AH and influences mortality at admission and after steroid initiation. These results emphasize the need for specific management of lung infection during the course of AH.

Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective Study.

BACKGROUND AND AIMS: Because of the extensive use of this drug, further evaluation of acute liver injury (ALI) with therapeutic doses of acetaminophen (APAP; ≤6 g/d) is required. We characterize ALI with therapeutic doses of APAP and determine the host factors associated with disease severity and the predictors of outcome. APPROACH AND RESULTS: All patients admitted with severe APAP-related ALI in our center were included from 2002 to 2019, either attributable to therapeutic doses or overdose. ALI with therapeutic doses (ALITD) was defined as APAP intake <6 g/d. Overall, 311 of 400 patients with APAP-related ALI had overdose and 89 had taken therapeutic doses. The host factors associated with ALITD were fasting ≥1 day (47.5% of ALITD patients vs. 26% in overdose; P = 0.001), excess drinking (93.3% vs. 48.5%; P < 0.0001), and repeated APAP use (4 vs. 1 day; P < 0.0001). Patients with ALITD were older (44 vs. 30.7 years; P < 0.0001) and had more severe liver injury. In the overall population, the independent predictors of disease severity were older age, longer duration of APAP, and excess drinking. Thirty-day survival was lower in ALITD than in overdose (87.2 ± 3.6% vs. 94.6 ± 1.3%; P = 0.02). Age and the presence of at least one of the King's College Hospital criteria were independent predictors of 30-day survival whereas the pattern of drug intoxication, excess drinking, and bilirubin were not. CONCLUSIONS: ALI with therapeutic doses of APAP is associated with more severe liver injury than overdose. It only occurs in patients with excess drinking and/or fasting. A warning should be issued about the repeated use of nontoxic doses of APAP in patients with those risk factors.

Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study.

BACKGROUND AND AIMS: To report 5-year outcomes of the CERTITUDE study. METHODS: An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. RESULTS: Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS: The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

Liver transplantation for NAFLD cirrhosis: Age and recent coronary angioplasty are major determinants of survival.

BACKGROUND AND AIMS: Liver transplantation (LT) is the treatment of end-stage non-alcoholic liver disease (NAFLD), that is decompensated cirrhosis and/or complicated by hepatocellular carcinoma (HCC). Few data on long-term outcome are available. The aim of this study was to evaluate overall patient and graft survivals and associated predictive factors. METHOD: This retrospective multicentre study included adult transplant patients for NAFLD cirrhosis between 2000 and 2019 in participating French-speaking centres. RESULTS: A total of 361 patients (69.8% of male) were included in 20 centres. The median age at LT was 62.3 years [57.4-65.9] and the median MELD score was 13.9 [9.1-21.3]; 51.8% of patients had HCC on liver explant. Between 2004 and 2018, the number of LT for NAFLD cirrhosis increased by 720%. A quarter of the patients had cardiovascular history before LT. Median follow-up after LT was 39.1 months [15.8-72.3]. Patient survival at 1, 5 and 10 years after LT was 89.3%, 79.8% and 68.1% respectively. The main causes of death were sepsis (37.5%), malignancies (29.2%) and cardiovascular events (22.2%). In multivariate analysis, three risk factors for overall mortality after LT were recipient pre-LT BMI < 32 kg/m2 at LT time (OR: 2.272; p = .012), pre-LT angioplasty during CV check-up (OR: 2.916; p = .016), a combined donor and recipient age over 135 years (OR: 2.020; 95%CI: p = .035). CONCLUSION: Survival after LT for NAFLD cirrhosis is good at 5 years. Donor and recipient age, and cardiovascular history, are major prognostic factors to consider.

The role of prehabilitation on short-term outcomes after liver transplantation: A review of the literature and expert panel recommendations.

BACKGROUND: Prehabilitation programs as part of ERAS protocols are being increasingly used in multiple surgeries, improving postoperative outcomes. Data regarding prehabilitation programs in patients awaiting liver transplantation and their outcomes is scarce. OBJECTIVES: To identify whether prehabilitation programs based on exercise training conducted prior to liver transplantation improve short-term postoperative outcomes, and to provide expert panel recommendations. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Studies included those evaluating postoperative outcomes, as well as those evaluating functional outcomes. PROSPERO ID: CRD42021236305. RESULTS: Of the 170 studies screened, only one assessed the primary objective. Most studies focus on the preoperative impact of exercise training on aerobic capacity, muscle mass and/or strength, showing positive effects and no significant adverse events, but are underpowered and with heterogenous designs and interventions. The non-randomized observational study which assessed relevant postoperative outcomes, showed a non-significant trend towards reduced 90-day readmission rate and shorter length of stay in the prehabilitation group. CONCLUSIONS: Prehabilitation prior to liver transplantation is unlikely to be harmful, and likely to have short term benefits on functional status. We cautiously recommend prehabilitation on the basis of absence of harm and possibility of benefit (Quality of Evidence; Very Low | Grade of Recommendation; Low).

Neo-Adjuvant Use of Sorafenib for Hepatocellular Carcinoma Awaiting Liver Transplantation.

Data on efficacy and safety of sorafenib in a neoadjuvant setting for HCC awaiting liver transplantation (LT) are heterogeneous and scarce. We aimed to investigate the trajectory of patients treated with sorafenib while awaiting LT. All patients listed for HCC and treated with sorafenib were included in a monocentric observational study. A clinical and biological evaluation was performed every month. Radiological tumor response evaluation was realized every 3 months on the waiting list and every 6 months after LT. Among 327 patients listed for HCC, 62 (19%) were treated with Sorafenib. Sorafenib was initiated for HCC progression after loco-regional therapy (LRT) in 50% of cases and for impossibility of LRT in 50% of cases. The mean duration of treatment was 6 months. Thirty six patients (58%) dropped-out for tumor progression and 26 (42%) patients were transplanted. The 5-year overall and recurrent-free survival after LT was 77% and 48% respectively. Patients treated for impossibility of LRT had acceptable 5-year intention-to-treat overall and post-LT survivals. Conversely, patients treated for HCC progression presented high dropout rate and low intention-to-treat survival. Our results suggest that it is very questionable in terms of utility that patients treated for HCC progression should even be kept listed once the tumor progression has been observed.

The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.

BACKGROUND: The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established. OBJECTIVE: To determine whether rifaximin prevents overt HE after TIPS compared with placebo. DESIGN: Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196). PARTICIPANTS: 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding. INTERVENTION: Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure. MEASUREMENTS: The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure. RESULTS: An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups. LIMITATIONS: The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. CONCLUSION: In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE. PRIMARY FUNDING SOURCE: French Public Health Ministry.

Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis.

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A. RESULTS: In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication. CONCLUSION: Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY: Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.

Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.

BACKGROUND AND AIMS: Studies are needed to determine the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). We evaluated sequential liver samples, collected the time of bariatric surgery and 1 and 5 years later, to assess the long-term effects of bariatric surgery in patients with NASH. METHODS: We performed a prospective study of 180 severely obese patients with biopsy-proven NASH, defined by the NASH clinical research network histologic scores. The patients underwent bariatric surgery at a single center in France and were followed for 5 years. We obtained liver samples from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. The primary endpoint was the resolution of NASH without worsening of fibrosis at 5 years. Secondary end points were improvement in fibrosis (reduction of ≥1 stage) at 5 years and regression of fibrosis and NASH at 1 and 5 years. RESULTS: At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. Persistence of NASH was associated with no decrease in fibrosis and less weight loss (reduction in body mass index of 6.3 ± 4.1 kg/m2 in patients with persistent NASH vs reduction of 13.4 ± 7.4 kg/m2; P = .017 with resolution of NASH). Resolution of NASH was observed at 1 year after bariatric surgery in biopsies from 84% of patients, with no significant recurrence between 1 and 5 years (P = .17). Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years (P < .001). CONCLUSIONS: In a long-term follow-up of patients with NASH who underwent bariatric surgery, we observed resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis is progressive, beginning during the first year and continuing through 5 years.