Tacrolimus Monitoring in Liver Transplant Recipients, Posttransplant Cholestasis: A Comparative Between 2 Commercial Immunoassays and a Liquid Chromatography-Tandem Mass Spectrometry Method.

BACKGROUND: Cholestasis commonly occurs after orthotopic liver transplantation. It can be extrahepatic because of mechanical obstruction or intrahepatic because of various causes. During cholestasis episodes, blood concentrations of tacrolimus (TAC) metabolites may increase, potentially affecting TAC concentrations measured by immunoassays. This study aimed to simultaneously evaluate the analytical performance of 2 TAC immunoassays, a quantitative microsphere system (QMS) immunoassay, and chemiluminescence microparticle immunoassay, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a reference method in liver transplant recipients. METHODS: This single-center study included 265 patients who underwent orthotopic liver transplantation. In total, 942 blood samples were collected. TAC trough concentrations were measured using LC-MS/MS and 2 immunoassays in parallel. The plasma concentrations of conjugated bilirubin were measured in all samples. The results were analyzed using Bland-Altman plots and Passing-Bablok regressions. RESULTS: The Bland-Altman plot analysis showed that the TAC QMS immunoassay has a significant bias (+37%) compared with LC-MS/MS, and this bias was higher in patients with cholestasis with hyperbilirubinemia (≤+70% in patients with conjugated bilirubin >150 µmol/L). In comparison, the chemiluminescence microparticle immunoassay showed acceptable analytical performance in patients with hyperbilirubinemia (bias <10%). CONCLUSIONS: In agreement with previous findings, the TAC QMS immunoassay showed a positive bias compared with LC-MS/MS. This bias is remarkably high in patients with cholestasis and hyperbilirubinemia, suggesting the cross-reactivity of TAC metabolites with the monoclonal antibody used in the QMS immunoassay.

HOPE Mitigates Ischemia-Reperfusion Injury in Ex-Situ Split Grafts: A Comparative Study With Living Donation in Pediatric Liver Transplantation.

Optimizing graft preservation is key for ex-situ split grafts in pediatric liver transplantation (PSLT). Hypothermic Oxygenated Perfusion (HOPE) improves ischemia-reperfusion injury (IRI) and post-operative outcomes in adult LT. This study compares the use of HOPE in ex-situ partial grafts to static cold storage ex-situ partial grafts (SCS-Split) and to the gold standard living donor liver transplantation (LDLT). All consecutive HOPE-Split, SCS-Split and LDLT performed between 2018-2023 for pediatric recipients were included. Post-reperfusion syndrome (PRS, drop ≥30% in systolic arterial pressure) and reperfusion biopsies served as early indicators of IRI. We included 47 pediatric recipients (15 HOPE-Split, 17 SCS-Split, and 15 LDLT). In comparison to SCS-Split, HOPE-Split had a significantly shorter cold ischemia time (CIT) (470min vs. 538 min; p =0.02), lower PRS rates (13.3% vs. 47.1%; p = 0.04) and a lower IRI score (3 vs. 4; p = 0.03). The overall IRI score (3 vs. 3; p = 0.28) and PRS (13.3% vs. 13.3%; p = 1) after HOPE-Split were comparable to LDLT, despite a longer CIT (470 min vs. 117 min; p < 0.001). Surgical complications, one-year graft, and recipient survival did not differ among the groups. In conclusion, HOPE-Split mitigates early IRI in pediatric recipients in comparison to SCS-Split, approaching the gold standard of LDLT.

ABO blood group does not influence Child-Pugh A cirrhosis outcome: An observational study from CIRRAL and ANRS CO12 CIRVIR cohorts.

BACKGROUND AND AIMS: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients. METHODS: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 µmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation¼ or « the occurrence of one or more parameters ¼ among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival. RESULTS: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1). CONCLUSION: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170.

External validation of the French alpha-fetoprotein model for hepatocellular carcinoma liver transplantation in a recent unicentric cohort - a retrospective study.

Prognostic models of liver transplantation (LT) for hepatocellular carcinoma (HCC) mainly derive from LT cohorts with numerous hepatitis C virus (HCV) patients. The AFP model, which is currently used in France to select LT candidates, was derived from a cohort of LT performed between 1988 and 2001, including a majority of HCV-positive recipients. The emergence of new direct-acting antiviral therapies and subsequent decrease of HCV incidence may change the generalizability of such models. We performed an external validation of the AFP model in a cohort of recipients transplanted between 2005 and 2018. Although multivariable analysis identified all three model's factors (AFP level, largest tumor size, number of nodules) as predictors of tumor recurrence, the AFP model showed poor discrimination and calibration in the present cohort. This poor performance could be related to significant differences between the derivation and the present cohort in terms of etiology, severity of underlying liver disease, tumor burden and differentiation, and use of neoadjuvant treatments. The present findings suggest that the decline of HCV-induced HCC among LT candidates may compromise the generalizability of the AFP model in more recent LT cohorts. Further studies are required for updating or building more robust prognostic models.

High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients.

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) occurs in 10%-20% of patients transplanted for HCC. The treatment of HCC recurrence after LT remains a challenge. Consecutive patients who underwent LT for HCC between 2005 and 2015 at our center were recruited. Characteristics of patients with recurrence, modalities of treatment and outcome were collected retrospectively. Patient survival was analyzed according to HCC recurrence therapeutic strategy. Among 306 transplanted patients, 43 patients (14.1%) developed recurrence with a median survival time after recurrence of 10.9 months (95%CI: 6.6-18.6). Survival of patients treated with Sorafenib (SOR) and everolimus (EVL) (n = 19) was significantly better than that of the group treated with other strategies (n = 24) (P = 0.001). Multivariable analysis demonstrated that SOR plus EVL therapy and absence of dissemination at diagnosis of recurrence were independent predictive factors of prolonged survival after recurrence. Among the patients who treated with EVL, survival of patients with controlled EVL blood trough levels ≥5 ng/ml was significantly better compared to those with EVL trough levels <5 ng/ml (P = 0.021). Combination therapy of sorafenib and everolimus was an independent predictor for better survival after HCC recurrence. Patients with controlled everolimus trough level ≥5 ng/ml might get the best survival benefit.

Liver Transplantation for Colorectal Liver Metastases: Current Management and Future Perspectives.

Patients with nonresectable liver metastases from colorectal cancer have few therapeutic options and a dismal prognosis. Although liver transplantation for this indication has historically a poor reputation, recent advances in the field of chemotherapy and immunosuppression have paved the way to revisit the concept. New data have shown promising results that need to be validated in several ongoing clinical trials. Since liver grafts represent a scarce resource, several new tools are being explored to expand the donor pool for this indication. The purpose of this review is to present all current available data and perspectives about liver transplantation for nonresectable liver metastases from colorectal cancer.

Strategies for liver transplantation during the SARS-CoV-2 outbreak: Preliminary experience from a single center in France.

Liver transplantation (LT) during the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging given the urgent need to reallocate resources to other areas of patient care. Available guidelines recommend reorganizing transplant care, but data on clinical experience in the context of SARS-CoV-2 pandemic are scarce. Thus, we report strategies and preliminary results in LT during the peak of the SARS-CoV-2 pandemic from a single center in France. Our strategy to reorganize the transplant program included 4 main steps: optimization of available resources, especially intensive care unit capacity; multidisciplinary risk stratification of LT candidates on the waiting list; implementation of a systematic SARS-CoV-2 screening strategy prior to transplantation; and definition of optimal recipient-donor matching. After implementation of these 4 steps, we performed 10 successful LTs during the peak of the pandemic with a short median intensive care unit stay (2.5 days), benchmark posttransplant morbidity, and no occurrence of SARS-CoV-2 infection during follow-up. From this preliminary experience we conclude that efforts in resource planning, optimal recipient selection, and organ allocation strategy are key to maintain a safe LT activity. Transplant centers should be ready to readapt their practices as the pandemic evolves.

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

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.

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

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 m2 and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m2 . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m2 ), 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 m2 ) 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 m2 ). 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.

Analysis of Liver Resection Versus Liver Transplantation on Outcome of Small Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma in the Setting of Cirrhosis.

This multicenter study compares the outcomes of patients with cirrhosis undergoing liver transplantation (LT) or liver resection (LR) between January 2002 and July 2015 who had intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA) found incidentally in the native liver. A total of 49 (65%) LT and 26 (35%) LR patients with cirrhosis and histologically confirmed iCCA/cHCC-CCA ≤5 cm were retrospectively analyzed. LT patients had significantly lower tumor recurrence (18% versus 46%; P = 0.01), for which the median diameter of the largest nodule (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12]; P = 0.006) and tumor differentiation (HR, 3.74; 95% CI 1.71-8.17; P = 0.001) were independently predictive. The LT group had significantly higher 5-year recurrence-free survival (RFS; 75% versus 36%; P = 0.004). In patients with tumors >2 cm but ≤5 cm, LT patients had a lower recurrence rate (21% versus 48%; P = 0.06) and a higher 5-year RFS (74% versus 40%; P = 0.06). Independent risk factors for recurrence were LT (protective; HR, 0.23; 95% CI, 0.07-0.82; P = 0.02), the median diameter of the largest nodule (HR, 1.10; 95% CI, 1.02-1.73; P = 0.007), and tumor differentiation (HR, 4.16; 95% CI, 1.37-12.66; P = 0.01). In the LT group, 5-year survival reached 69% and 65% (P = 0.40) in patients with tumors ≤2 cm and >2-5 cm, respectively, and survival was also comparable between iCCA and cHCC-CCA patients (P = 0.29). LT may offer a benefit for highly selected patients with cirrhosis and unresectable iCCA/cHCC-CCA having tumors ≤5 cm. Efforts should be made to evaluate tumor differentiation, and these results need to be confirmed prospectively in a larger population.

Liver transplantation in patients with liver failure related to exertional heatstroke.

BACKGROUND & AIMS: Severe acute liver injury is a grave complication of exertional heatstroke. Liver transplantation (LT) may be a therapeutic option, but the criteria for LT and the optimal timing of LT have not been clearly established. The aim of this study was to define the profile of patients who require transplantation in this context. METHODS: This was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related severe acute liver injury with a prothrombin time (PT) of less than 50%. A total of 24 male patients were studied. RESULTS: Fifteen of the 24 patients (median nadir PT: 35% [29.5-40.5]) improved under medical therapy alone and survived. Nine of the 24 were listed for emergency LT. At the time of registration, the median PT was 10% (5-12) and all had numerous dysfunctional organs. Five patients (nadir PT: 12% [9-12]) were withdrawn from the list because of an elevation of PT values that mainly occurred between day 2 and day 3. Ultimately, 4 patients underwent transplantation as their PT persisted at <10%, 3 days (2.75-3.25) after the onset of exertional heatstroke, and they had more than 3 organ dysfunctions. Of these 4 patients, 3 were still alive 1 year later. Histological analysis of the 4 explanted livers demonstrated massive or sub-massive necrosis, and little potential for effective mitoses, characterised by a "mitonecrotic" appearance. CONCLUSION: The first-line treatment for exertional heatstroke-related severe acute liver injury is medical therapy. LT is only a rare alternative and such a decision should not be taken too hastily. A persistence of PT <10%, without any signs of elevation after a median period of 3  days following the onset of heatstroke, was the trigger that prompted LT, was the trigger adopted in order to decide upon LT. LAY SUMMARY: Acute liver injury due to heatstroke can progress to acute liver failure with organ dysfunction despite medical treatment; in such situations, liver transplantation (LT) may offer a therapeutic option. The classic criteria for LT appear to be poorly adapted to heatstroke-related acute liver failure. We confirmed thatmedication is the first-line therapy acute liver injury caused by heatstroke, with LT only rarely necessary. A decision to perform LT should not be made hastily. Fluctuations in prothrombin time and the patient's clinical status should be considered even in the event of severe liver failure.

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.

BACKGROUND & AIMS: Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). METHODS: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. RESULTS: In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. CONCLUSIONS: Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. LAY SUMMARY: Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.

Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.

BACKGROUND & AIMS: More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. METHODS: Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). RESULTS: From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients' inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5-95.4), 80.3% (95% CI 76.9-83.9), and 3.2% (95% CI 1.6-4.8) respectively. CONCLUSION: This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. LAY SUMMARY: Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening.

Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-on-chronic liver failure grade 3.

BACKGROUND & AIMS: Liver transplantation (LT) for the most severely ill patients with cirrhosis, with multiple organ dysfunction (accurately assessed by the acute-on-chronic liver failure [ACLF] classification) remains controversial. We aimed to report the results of LT in patients with ACLF grade 3 and to compare these patients to non-transplanted patients with cirrhosis and multiple organ dysfunction as well as to patients transplanted with lower ACLF grade. METHODS: All patients with ACLF-3 transplanted in three liver intensive care units (ICUs) were retrospectively included. Each patient with ACLF-3 was matched to a) non-transplanted patients hospitalized in the ICU with multiple organ dysfunction, or b) control patients transplanted with each of the lower ACLF grades (three groups). RESULTS: Seventy-three patients were included. These severely ill patients were transplanted following management to stabilize their condition with a median of nine days after admission (progression of mean organ failure from 4.03 to 3.67, p=0.009). One-year survival of transplanted patients with ACLF-3 was higher than that of non-transplanted controls: 83.9 vs. 7.9%, p<0.0001. This high survival rate was not different from that of matched control patients with no ACLF (90%), ACLF-1 (82.3%) or ACLF-2 (86.2%). However, a higher rate of complications was observed (100 vs. 51.2 vs. 76.5 vs. 74.3%, respectively), with a longer hospital stay. The notion of a "transplantation window" is discussed. CONCLUSIONS: LT strongly influences the survival of patients with cirrhosis and ACLF-3 with a 1-year survival similar to that of patients with a lower grade of ACLF. A rapid decision-making process is needed because of the short "transplantation window" suggesting that patients with ACLF-3 should be rapidly referred to a specific liver ICU. Lay summary: Liver transplantation improves survival of patients with very severe cirrhosis. These patients must be carefully monitored and managed in a specialized unit. The decision to transplant a patient must be quick to avoid a high risk of mortality.

A new definition of sarcopenia in patients with cirrhosis undergoing liver transplantation.

Although sarcopenia is a common complication of cirrhosis, its diagnosis remains nonconsensual: computed tomography (CT) scan determinations vary and no cutoff values have been established in cirrhotic populations undergoing liver transplantation (LT). Our aim was to compare the accuracy of the most widely used measurement techniques and to establish useful cutoffs in the setting of LT. From the 440 patients transplanted between January 2008 and May 2011 in our tertiary center, we selected 256 patients with cirrhosis for whom a recent CT scan was available during the 4 months prior to LT. We measured different muscle indexes: psoas muscle area (PMA), PMA normalized by height or body surface area (BSA), and the third lumbar vertebra skeletal muscle index (L3SMI). Receiver operating characteristic curves were evaluated and prognostic factors for post-LT 1-year survival were then analyzed. PMA offered better accuracy (area under the curve [AUC] = 0.753) than L3SMI (AUC = 0.707) and PMA/BSA (AUC = 0.732), and the same accuracy as PMA/squared height. So, for its accuracy and simplicity of use, the PMA index was used for the remainder of the analysis and to define sarcopenia. In men, the better cutoff value for PMA was 1561 mm2 (Se = 94%, Sp = 57%), whereas in women, it was 1464 mm2 (Se = 52%, Sp = 91%). A PMA lower than these values defined sarcopenia in patients with cirrhosis awaiting LT. One- and 5-year overall survival rates were significantly poorer in the sarcopenic group (n = 57) than in the nonsarcopenic group (n = 199), at 59% versus 94% and 54% versus 80%, respectively (P < 0.001). In conclusion, pre-LT PMA is a simple tool to assess sarcopenia. We established sex-specific cutoff values (1561 mm2 in men, 1464 mm2 in women) in a cirrhotic population and showed that 1-year survival was significantly poorer in sarcopenic patients. Liver Transplantation 23 143-154 2017 AASLD.

Albumin Use in Patients With Cirrhosis in France: Results of the "ALBU-LIVE" Survey: A Case for Better EASL Guidelines Diffusion and/or Revision.

INTRODUCTION: The use of human albumin for the management of cirrhosis has increased. Recommendations have been published for therapeutic paracentesis (TP), spontaneous bacterial peritonitis (SBP), and type 1 hepatorenal syndrome (HRS). The goal of this survey was to assess the prescription practices of French hepatogastroenterologists. METHODS: All hepatogastroenterologists were contacted. The questionnaire evaluated (1) the use of albumin in validated indications and (2) the prescription of albumin for nonvalidated clinical situations. RESULTS: Responses were analyzed from 451 (50.1%) practitioners. The mean age was 40 years (range, 24 to 67 y). Physicians practiced in a university hospital (47.7%) or a general hospital (45.8%). There were 56.7% senior practitioners. Overall 99.6% of the practitioners compensated for TP. Albumin was used by 87.8% of the physicians, with a fixed dose being used by 84.6%. For SBP, 94% of the physicians used albumin concomitantly with antibiotics. The recommended protocol was followed by 56.2% of the practitioners: more often by senior university hospital practitioners than by senior general hospital practitioners (P=0.015). About 66.5% used albumin infusion for the diagnosis of HRS: used more often by senior university hospital practitioners (P=0.0006). Albumin was used concomitantly with vasopressor treatment by 84%; the dose and the duration varied considerably. About 23.5% used albumin for severe bacterial infection, 47.9% for severe hyponatremia, 43.9% for severe hypoalbuminemia, and 65.9% for hydrothorax. CONCLUSIONS: In this large French survey, albumin is only prescribed in accordance with recommendations for TP. The schedule for SBP is followed by only 56% of the practitioners. The use of albumin for HRS is not adapted to recommendations, which are not well known, suggesting that they should be more diffused.

Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge.

Sofosbuvir and daclatasvir are direct-acting antiviral drugs used to treat chronic hepatitis C virus infection. In 2015, the Food and Drug Administration and European Medical Agency warned that bradycardia could occur when amiodarone was administered in combination with sofosbuvir, but no case reports had been published. We report extreme bradycardia within 2 hrs after intake of sofosbuvir and daclatasvir by 2 patients receiving amiodarone. The first patient had a cardiac asystole 30 min after receiving sofosbuvir and daclatasvir. Amiodarone, sofosbuvir, and daclatasvir treatment were stopped; after 10 days, the cardiac evaluation was normal and patient was discharged. The second patient was taking amiodarone and propranolol; 2 hrs after receiving sofosbuvir and daclatasvir, he had an extreme sinus node dysfunction (heart rate of 27beats/min). Amiodarone and propranolol were stopped, but the patient continued receiving sofosbuvir and daclatasvir for 3 days and sinus bradycardia was recorded each day, 2 hrs after intake of these drugs. When he stopped taking the drugs, no bradycardia was observed. Administration of sofosbuvir and daclatasvir on day 13 induced bradycardia 2 hrs after intake. However, no bradycardia occurred following a rechallenge 8 weeks after the patient stopped taking amiodarone. These observations indicate that patients treated with amiodarone should be continuously monitored within the first 48 hrs following the initiation of sofosbuvir and daclatasvir.

Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria.

In France, decisions regarding superurgent (SU) liver transplantation (LT) for patients with acute liver failure (ALF) are principally based on the Clichy-Villejuif (CV) criteria. The aims of the present study were to study the outcomes of patients registered for SU LT and the factors that were predictive of spontaneous improvement and to determine the usefulness of the CV criteria. All patients listed in France for SU LT between 1997 and 2010 who were 15 years old or older with ALF were included. In all, 808 patients were listed for SU transplantation: 22% with paracetamol-induced ALF and 78% with non-paracetamol-induced ALF. Of these 808 patients, 112 improved spontaneously, 587 underwent LT, and 109 died or left the waiting list because of a worsening condition. The 1-year survival rate according to an intention-to-treat analysis and the survival after LT were 66.3% [interquartile range (IQR), 62.7%-69.7%] and 74.2% (IQR, 70.5%-77.6%), respectively. The factors that were predictive of a spontaneous recovery with ALF-related paracetamol hepatotoxicity were as follows: hepatic encephalopathy grade 0, 1, or 2 [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.99-11.6]; creatinine clearance≥60 mL/minute/1.73 m2 (OR, 4.77; 95% CI, 1.96-11.63), a bilirubin level<200 µmol/L (OR, 21.64; 95% CI, 1.76-265.7); and a factor V level>20% (OR, 5.79; 95% CI, 1.66-20.29). For ALF-related nonparacetamol hepatotoxicity, the factor that was predictive of a spontaneous recovery was a bilirubin level<200 µmol/L (OR, 10.38; 95% CI, 4.71-22.86). The sensitivity, specificity, and positive and negative predictive values for the CV criteria were 75%, 56%, 50%, and 79%, respectively, for ALF due to paracetamol and 69%, 50%, 64%, and 55%, respectively, for ALF not related to paracetamol. The performance of current criteria for SU transplantation could be improved if paracetamol-induced ALF and non-paracetamol-induced ALF were split and 2 other items were included in this model: the bilirubin level and creatinine clearance.

Hepatitis E infection in patients with severe acute alcoholic hepatitis.

BACKGROUND & AIMS: Hepatitis E virus (HEV) infection is a known cause of acute-on-chronic liver failure in developing countries, but its implication in Western countries remains unknown. HEV burden in the setting of severe acute alcoholic hepatitis (AAH) was assessed. METHODS: Patients admitted for severe AAH from 2007 to 2013, with available sera and histologically proven AAH, were included and managed according to current European guidelines. At admission, clinical and biological characteristics were collected; HEV serology and RNA detection were retrospectively performed. RESULTS: Eighty-four patients were included. Mean age was 50.8 ± 9.6 years, 65.5% were male, 91.7% were cirrhotic and 33.3% presented with encephalopathy. Mean MELD and Maddrey scores were respectively 32.4 ± 11.4 and 73.3 ± 37. Liver biopsy showed mild, moderate and severe hepatitis in 25 (29.8%), 23 (27.4%) and 32 (38.1%) patients respectively. Steroids were given to 61 patients (72.6%) of whom 35 (57.4%) presented corticoresistance (mean Lille score: 0.78 ± 0.21). During hospitalization, 24 patients (28.6%) died and 11 (13.1%) were transplanted. Three patients (3.6%) presented markers of acute HEV infection and 21 (25%) markers of past HEV infection. Patient with acute infection were men, cirrhotic, and 2/3 presented with encephalopathy. Steroids were given to two patients without any response. The third patient died. None were transplanted. CONCLUSIONS: A substantial proportion of patients with severe AAH had markers of acute HEV infection, with similar clinical presentation and outcomes. Larger studies are needed to evaluate HEV impact on AAH management, resistance to steroids, and outcome.