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Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.

First reported in 1976, hepatic angiomyolipoma (HAML) is a rare mesenchymal liver tumor occurring mostly in middle-aged women. Diagnosis of the liver mass is often incidental on abdominal imaging due to the frequent absence of specific symptoms. Nearly 10% of HAMLs are associated with tuberous sclerosis complex. HAML contains variable proportions of blood vessels, smooth muscle cells and adipose tissue, which renders radiological diagnosis hazardous. Cells express positivity for HMB-45 and actin, thus these tumors are integrated into the group of perivascular epithelioid cell tumors. Typically, a HAML appears on magnetic resonance imaging (or computed tomography scan) as a hypervascular solid tumor with fatty areas and with washout, and can easily be misdiagnosed as other liver tumors, particularly hepatocellular carcinoma. The therapeutic strategy is not clearly defined, but surgical resection is indicated for symptomatic patients, for tumors showing an aggressive pattern (i.e., changes in size on imaging or high proliferation activity and atypical epithelioid pattern on liver biopsy), for large (> 5 cm) biopsy-proven HAML, and if doubts remain on imaging or histology. Conservative management may be justified in other conditions, since most cases follow a benign clinical course. In summary, the correct diagnosis of HAML is challenging on imaging and relies mainly on pathological findings.

Alcohol-related cirrhosis is a frequent and difficult-to-treat disease. Despite the low hepatic metabolism of baclofen, data on its use in this subgroup are scarce. The French multicenter Observatory of patients treated with Baclofen for Alcohol DEpendence real-life cohort assessed: (a) prescription modalities of baclofen in liver units; (b) safety profile of baclofen; and (c) declared alcohol intake, biological markers of excessive alcohol intake and hepatic function at 12 months.All consecutive patients with cirrhosis who received baclofen to reduce alcohol consumption or maintain abstinence were prospectively included. Psychosocial management was always associated. Clinical and biological data were collected every 3 months for 1 year.Between November 2013 and December 2016, 71 in- or outpatients were included from 10 liver units. Of the patients, 25% had ascites. After 12 months, 52 patients (73%) were still being followed, and 41 (57.7%) were still receiving baclofen at a mean dosage of 75 mg/day (r30-210). The overall declared consumption decreased from 100.2 to 14.7 g/day (P 0.0001), and 29 patients (40.8%) reached abstinence. Significant improvement in the usual biomarkers of excessive alcohol intake (AST, GGT and MCV) and liver function (Prothrombin ratio (PTr), albumin levels) were observed. The usual side effects such as drowsiness were frequent (22%) but no serious adverse events (AEs) or overt encephalopathy related to baclofen was reported.In this 1-year follow-up series, baclofen was combined with psychosocial treatment in patients with cirrhosis and was well tolerated. This treatment was associated with a significant decrease in declared alcohol consumption as well as improvement in hepatic function.

International audience; BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use. AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients. METHODS A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naive, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors. RESULTS Of the 196 patients analyzed, 138 (84 naive, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naive and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m(2) or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naive, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naive group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naive, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo. CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naive patients. SPT in the naive population suggests that HBV can induce renal tubular toxicity.

The management of inflammatory rheumatic diseases has substantially changed in recent years, as has the profile of patients. The advent of biotherapies has been a revolution in rheumatology and the impact of co-morbidities in the management of these patients is now becoming increasingly important. Metabolic syndrome (MetS) is one of the most frequent comorbidities, and hepatic complications of MetS are not uncommon. MetS is responsible for Non-alcoholic fatty liver disease (NAFLD), characterized by excessive hepatic fat accumulation. In extreme cases, progression to cirrhosis is possible. NAFLD ranks among the top three indications for liver transplantation. We review available data on the safety, especially the risk of infections, of TNF inhibitors (TNFi) in case of NAFLD and in case of liver cirrhosis, in patients with rheumatic disease. In cases of NAFLD without severe fibrosis, available data are reassuring and tend to show a beneficial effect of TNFi on hepatic tissue. In case of cirrhosis, data are conflicting. Further large, well-designed studies are needed to explore this specific issue.

A 64-year-old cirrhotic woman was admitted for alcoholic hepatitis associated with renal failure. Subsequently, she displayed symptoms of alcohol withdrawal progressing to delirium tremens. During hospitalization, she developed acute respiratory distress. The electrocardiogram showed diffuse anteroseptal ST elevation. Transthoracic echocardiography revealed systolic left ventricular apical balloon-like dilation, hypokinesis of the left ventricular mid- and apical segments, and a left ventricular ejection fraction of 30%. Coronary angiography was normal and led to the diagnosis of Takotsubo cardiomyopathy. This report describes a singular case of Takotsubo cardiomyopathy precipitated by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure.

Background & Aims Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. Methods Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). Results Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24–0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33–0.46), and CSRmax was negatively correlated with CP score (r = −0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min−1) compared with that in the CP ≤8 group (0.21 ± 0.21 min−1), and free cortisol elimination rates were negatively correlated with CP score (r = −0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p, Graphical abstract, Highlights • Free cortisol appearance and elimination rates were obtained by computer-assisted numerical analysis. • Maximal cortisol secretion rates, a measure of adrenocortical function, were inversely related to severity of cirrhosis. • Variation in concentrations of cortisol binding proteins bias measures of adrenocortical function that rely on total cortisol. • Chronically reduced rate of free cortisol elimination in patients with cirrhosis may contribute to the pathophysiology of subnormal adrenocortical function. • Evidence of subnormal adrenocortical function supports the hepatoadrenal syndrome hypothesis.

International audience; BACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.

BACKGROUND: In patients with autoimmune hepatitis (AIH), relapse rates between 25 and 100% after treatment withdrawal have been reported. The optimal strategy for immunosuppressive treatment withdrawal is controversial. AIM: To identify the predictive factors of histological remission and to assess the relapse rate after treatment withdrawal in AIH patients with prolonged biochemical response. METHODS: Patients with AIH and sustained biochemical remission on first-line treatment were retrospectively included. Histological response was defined as complete regression of interface hepatitis and lobular necrosis and no or minimal portal inflammation and relapse as any elevation of serum aminotransferase or gammaglobulin/IgG levels. RESULTS: Sixty-two patients were included. Forty-seven had a biopsy after a median biochemical response of 49.7 months. Twenty-five of them were histological responders. Independent predictors of histological remission were older age (OR = 1.1; CI 95%: 1.0; 1.2), mild-to-moderate fibrosis at diagnosis (OR = 8; CI: 1.4; 47.6) and aspartate aminotransferases

International audience

We read with interest the manuscript by Izzy and colleagues [1]. The authors carried out a retrospective study that mainly aimed to investigate the impact of cirrhotic cardiomyopathy (CCM, based on the recently revised criteria [2]) on new post-transplant cardiovascular (CV) disease outcomes. After 5 years of follow-up, patients with CCM had a 2.5-fold increase in the risk of new CV disease, and lower CV-disease-free survival (60.7% versus 85.2% in those without CCM). These novel results are of prime importance but deserve comment.

Purpose To describe the computed tomography (CT) and magnetic resonance imaging (MRI) features of severe acute alcoholic hepatitis (SAAH) and estimate the capabilities of CT and MRI in differentiating SAAH from alcoholic cirrhosis and non-alcoholic steato-hepatitis (NASH) cirrhosis. Materials and methods Fifty patients with pathologically proven SAAH (SAAH group) who underwent CT or MRI examinations up to 30 days before or 15 days after liver biopsy between January 2008 and June 2018 were retrospectively included. There were 31 men and 29 women with a mean age of 52 ± 9 (SD) years (range: 33–67 years). Imaging features of the SAAH group were compared to those obtained in two control groups including 62 patients with alcoholic cirrhosis without acute alcoholic hepatitis (control group 1) and 19 patients with NASH cirrhosis (control group 2) by two independent radiologists blinded to the final diagnosis. Univariate analyses were performed to compare imaging characteristics between the three groups, followed by diagnostic performance analysis for the diagnosis of SAAH of the main CT features. Results Heterogeneous steatosis was significantly more frequent in SAAH group than in the control groups (41/50; 82% vs. 7/62; 10% and 1/19; 5% in control groups 1 and 2, respectively for reader 1 and 34/50; 68% vs. 8/62; 13% and 1/19; 5% in control groups 1 and 2, respectively for reader 2; both P = 0.01). Transient perfusion disorders were more frequent in SAAH group than in the control groups (35/50; 70% vs. 12/62; 21% and 5/19; 26% in control groups 1 and 2, respectively for reader 1 and 39/50; 78% vs. 14/62; 23% and 13/19; 6% in control groups 1 and 2, respectively for reader 2; both P = 0.01). The combination of these two findings yielded 100% specificity (45/45; 95% CI: 92–100) for readers 1 and 2 for the diagnosis of SAAH vs. alcoholic cirrhosis and NASH cirrhosis. Conclusion The imaging features of SAAH are specific and mainly associate transient heterogeneous steatosis and liver perfusion disorders. CT/MRI may be useful to differentiate SAAH from alcoholic cirrhosis and NASH cirrhosis.

The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

Summary Background and aims The reported hepatotoxicity of methotrexate underlines the need for a repeated non-invasive and reliable evaluation of liver fibrosis. We estimated, using a non-invasive strategy, the prevalence of significant liver fibrosis in patients treated by methotrexate and the predictors of significant fibrosis (fibrosis ≥ F2). Methods Fibrosis was prospectively evaluated using 9 non-invasive tests in consecutive patients with psoriasis, rheumatoid arthritis, or Crohn's disease. Significant fibrosis was assessed without liver biopsy by defining a “specific method” (result given by the majority of the tests) and a “sensitive method” (at least one test indicating a stage ≥ F2). Results One hundred and thirty-one patients (66 Psoriasis, 40 rheumatoid arthritis, and 25 Crohn's disease) were enrolled, including 83 receiving methotrexate. Seven tests were performed on average per patient, with a complete concordance in 75% of cases. Fibroscan® was interpretable in only 61% of patients. The best performances (AUROC > 0.9) for predicting significant fibrosis were obtained by tests dedicated to steatohepatitis (FibroMeter NAFLD, NFS and FPI). The prevalence of fibrosis ≥ F2 according to the “specific” or the “sensitive” assessment of fibrosis was 10% and 28%, respectively. Methotrexate exposure did not influence the fibrosis stage. Factors independently associated with significant fibrosis according our “sensitive method” were age, male gender, and metabolic syndrome. Conclusion We provided a non-invasive approach for identifying liver fibrosis ≥ F2 by using 8 biochemical tests and Fibroscan®. In this population, the risk of significant fibrosis was related to age, male gender, and presence of metabolic syndrome, but was not influenced by methotrexate.

AIM We aimed to evaluate the accuracy of the dosage of calprotectin in ascitic fluid (AF) using the Quantum Blue assay, for the prompt diagnosis of spontaneous bacterial peritonitis (SBP). METHODS We prospectively collected 236 AF samples from 119 cirrhotic patients hospitalized in two French centers between May 2016 and May 2017. Bloody and chylous/cloudy AF, and secondary peritonitis were excluded. SBP was diagnosed if neutrophils in AF were >250/mm3 using standard cytology. The Quantum Blue Reader selectively measured the calprotectin antigen (MRP8/14) in 12 min within the measurable range from 0.18 to 1.80 μg/mL; values outside this range were registered as 0.17 and 1.81 μg/mL. RESULTS A total of 36 AF were considered as SBP (15.2%). SBP had higher median levels of calprotectin than non-SBP (1.81 vs. 0.25 μg/mL, P

IF 4.5; International audience; Background & AimsThe quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3‐hydroxymyristate (3‐HM), a lipid component of LPS, and to evaluate correlations between 3‐HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage.MethodsPlasma from 90 noninfected cirrhotic patients (30 Child‐Pugh [CP]‐A, 30 CP‐B, 30 CP‐C) was prospectively collected. The concentration of 3‐HM was determined by high‐performance liquid chromatography coupled with mass spectrometry.Results3‐HM levels were higher in CP‐C patients (CP‐A/CP‐B/CP‐C: 68/70/103 ng/mL, P = 0.005). Patients with severe acute alcoholic hepatitis (n = 16; 113 vs 74 ng/mL, P = 0.012), diabetic patients (n = 22; 99 vs 70 ng/mL, P = 0.028) and those not receiving beta blockers (n = 44; 98 vs 72 ng/mL, P = 0.034) had higher levels of 3‐HM. We observed a trend towards higher baseline levels of 3‐HM in patients with hepatic encephalopathy (n = 7; 144 vs 76 ng/mL, P = 0.45) or SIRS (n = 10; 106 vs 75 ng/mL, P = 0.114). In multivariate analysis, high levels of 3‐HM were associated with CP (OR = 4.39; 95%CI = 1.79‐10.76) or MELD (OR = 8.24; 95%CI = 3.19‐21.32) scores. Patients dying from liver insufficiency (n = 6) during a 12‐month follow‐up had higher baseline levels of 3‐HM (106 vs 75 ng/mL, P = 0.089).ConclusionsIn noninfected cirrhotic patients, 3‐HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, nonuse of beta blockers and a trend towards poorer outcome is also observed. The direct mass measurement of LPS using 3‐HM appears reliable to detect transient endotoxaemia and promising to manage the follow‐up of cirrhotic patients.

Introduction Microvesicles (MVs) with procoagulant properties may favor liver parenchymal extinction, then cirrhosis-related complications and mortality. In a longitudinal cohort of cirrhotic patients, we measured plasma levels of platelet-derived MVs (PMVs), endothelial-derived MVs, and red blood cell-derived MVs, expressing phosphatidylserine (annexin V-positive [AV+]) or not, and evaluated their impact on Model for End-Stage Liver Disease (MELD) score and transplant-free survival. Methods MVs were quantified using flow cytometry in plasma from 90 noninfected cirrhotic patients and 10 healthy volunteers matched for age and sex. Impact of plasma microvesicle levels on 6-month transplant-free survival was assessed using log-rank tests and logistic regression. Results Microvesicle levels, mostly platelet-derived, were 2.5-fold higher in healthy volunteers compared with cirrhotic patients. Circulating small AV+ PMV levels were lower in cirrhotic patients (P = 0.014) and inversely correlated with MELD scores (R = -0.28; P = 0.0065). During 1-year follow-up, 8 patients died and 7 underwent liver transplantation. In the remaining patients, circulating microvesicle levels did not change significantly. Six-month transplant-free survival was lower in patients with low baseline small AV+ PMV levels (72.6% vs 96.2%; P = 0.0007). In multivariate analyses adjusted for age, ascites, esophageal varices, encephalopathy, clinical decompensation, total platelet counts, MELD score, and/or Child-Pugh C stage, patients with lower small AV+ PMV levels had a significant 5- to 8-fold higher risk of 6-month death or liver transplant. Other PMV levels did not impact on survival. Discussion Decreased circulating small AV+ PMV levels are associated with significantly lower transplant-free survival in cirrhotic patients independently of MELD score and platelet counts.

Biliary complications represent a turning point in the course of Alveolar Echinococcosis (AE). We conducted a European survey to collect data on the current usage and results of perendoscopic interventions (PEIs) for their treatment.Patient's characteristics and follow-up until January 31st, 2015 were recorded using an online questionnaire.From 18 centers 129 PEIs were analyzed in 38 patients; 139 plastic stents were inserted during 85 PEIs; median time between stent placements was significantly longer when 3 stents or more were placed. Initial symptoms disappeared in 95% and long-term bile duct patency was obtained in 73% of cases. Cholangitis was a more frequent complication of the PEIs (10%) than in other indications; intensive lavage of the bile ducts may prevent this complication.European centers use perendoscopic biliary drainage as an efficient and safe alternative to surgery to treat AE biliary complications. Insertion of multiple plastic stents delays stent occlusion and leads to effective and prolonged bile duct patency.

Background/aims The variations in C-reactive protein (CRP) levels have been reported to have prognostic significance in decompensated cirrhotic patients. We aimed to provide an external validation of a prognostic model combining model for end-stage liver disease (MELD) and 'sustained high CRP levels' as main variables and to optimize the model to the context of liver transplantation by focusing on 3-month mortality with no consideration of severe chronic extrahepatic diseases. Patients and methods Data from cirrhotic patients enrolled in the CANONIC study were collected. Multivariate analyses used the competing risk model. The prognostic performance [area under receiver operating characteristic curve (AUROC)] of the model incorporating CRP variations within 15 days was compared with that of the MELD score alone. Results 583 decompensated cirrhotic patients with Child-Pugh more than B7 and serial CRP measures available were included. Of these, 111 patients had baseline CRP at least 29 mg/l and 60 still had CRP at least 29 mg/l at day 15 +/- 6 (group A). Multivariate analysis (competing risk) identified three predictors of 3-month mortality: high MELD score [hazard ratio (HR) = 1.14; 95% confidence intervals (CI): 1.11-1.17, P

Points essentiels Le syndrome hepato-pulmonaire (SHP) est defini par l’association d’une hypertension portale, d’un gradient alveolo-arteriel en oxygene eleve et de dilatations vasculaires intra-pulmonaires. Les mecanismes physiopathologiques de l’hypoxemie se caracterisent par des anomalies du rapport ventilation/perfusion (soit des zones d’effet shunt, dues au fait que des vaisseaux tres dilates sont trop perfuses par rapport a la ventilation, soit des zones de shunt anatomique, dues a des neo-vaisseaux pulmonaires, perfuses mais pas ventiles) et des troubles de la diffusion de l’oxygene. L’exces de mediateurs vasodilatateurs (comme le monoxyde d’azote) et de facteurs pro-angiogeniques (comme le VEGF) jouent un role majeur dans la survenue d’un SHP. Les symptomes sont aspecifiques et domines par une dyspnee, surtout en position debout, qui se majore progressivement. Un SHP severe peut etre suspecte devant une diminution de la saturation en oxygene. Les traitements medicamenteux restent decevants et seule la transplantation hepatique permet la resolution du SHP. La survie post-transplantation est excellente si l’hypoxemie avant la greffe de foie n’est pas trop profonde.

Introduction L’hepatotoxicite rapportee avec le methotrexate souligne la necessite d’une evaluation repetee, non invasive et fiable de la fibrose hepatique. Nous avons depiste, par une strategie non invasive chez des patients traites par methotrexate, la prevalence et les facteurs predictifs d’une fibrose hepatique significative (fibrose ≥ F2). Materiel et methodes La fibrose a ete depistee prospectivement en utilisant 9 tests non invasifs chez des patients consecutifs atteints de psoriasis, de polyarthrite rhumatoide ou de maladie de Crohn. La fibrose significative a ete evaluee sans biopsie hepatique en definissant une « methode specifique » (resultat donne par la majorite des tests) et une « methode sensible » (au moins un test indiquant un stade ≥ F2). Resultats Un total de 131 patients (66 psoriasis, 40 polyarthrite rhumatoide et 25 maladie de Crohn) ont ete recrutes, dont 83 recevaient du methotrexate. Sept tests ont ete realises en moyenne par patient, avec une concordance complete dans 75 % des cas. Le Fibroscan® etait interpretable chez seulement 61 % des patients. Les meilleures performances (AUROC > 0,9) pour predire une fibrose significative ont ete obtenues par des tests dedies a la steatohepatite (FibroMeter NAFLD, NFS et FPI). La prevalence de la fibrose ≥ F2 selon la methode « specifique » ou « sensible » de la fibrose etait respectivement de 10 % et 28 %. L’exposition au methotrexate n’influencait pas le stade de la fibrose. Selon notre « methode sensible », les facteurs independamment associes a une fibrose significative etaient l’âge, le sexe masculin et le syndrome metabolique. Discussion Nous avons donc defini chez les patients traites par methotrexate, une approche non invasive pour identifier la fibrose hepatique significative (≥ F2) en utilisant 8 tests biochimiques et le Fibroscan®. Dans cette population, le risque de fibrose importante etait lie a l’âge, au sexe masculin et a la presence d’un syndrome metabolique, mais n’etait pas influence par le methotrexate.

Background The management of inflammatory rheumatisms and psoriasis has largely evolved over the last 15 years with the emergence of biotherapies whose main adverse effect is the increased infection risk. The prevalence of metabolic syndrome is increasing and has been estimated at 30% in patients with rheumatoid arthritis with an excess of 45% compared to healthy subjects. One of the major complications of the metabolic syndrome is the Non Alcoholic Fatty Liver Disease (NAFLD), which prevalence is 25% in the global population, and 30% in a cohort of patients with rheumatoid arthritis. The main complication of NAFLD is the development of cirrhosis, known to increase infectious risk. Surprisingly, there are no data on the safety of TNF antagonists in patients with chronic inflammatory disease and NAFLD or cirrhosis. Objectives To assess infectious and liver safety of the main TNF blockers used in chronic inflammatory diseases in patients with cirrhosis or NAFLD. Methods A systematic review of the literature, following the Prisma recommendations, was conducted on the Pubmed and Embase databases with the following keywords: ”adalimumab”, ”infliximab”, ”etanercept”, ”certolizumab”, ”golimumab” ”TNF -blockers “AND” liver cirrhosis ”,” non alcoholic fatty liver disease “. We selected only studies including patients treated with TNF blockers and with cirrhosis or ultrasonically characterised NAFLD. We excluded animal models and non-English articles. Results We identified 39 articles and only 11 fulfilled the inclusion criteria. 9 Case Reports have reported the tolerance of TNF-blockers in patients with cirrhosis and one controlled study (44 patients) assessed the safety of etanercept in case of NAFLD. One study (7 patients) investigated the impact of infliximab in refractory autoimmune hepatitis. The cause of cirrhosis was primary biliary cholangitis (5 cases), alpha1 antitrypsin deficiency (4 cases) and post hepatitis B cirrhosis (2 cases). All cirrhosis were compensated. Inflammatory diseases requiring the introduction of TNF blocker were rheumatoid arthritis (n=5), psoriatic arthritis (n=4), ulcerative colitis (n=2) and psoriasis (n=44). The TNF-blockers prescribed were adalimumab in 2 patients, infliximab in 11 patients and etanercept in 49 patients. The duration of treatment ranged from 6 to 24 months. For the 9 cirrhotic patients with an inflammatory disorder, no infection was reported and two of them (2 cases of primary biliary cholangitis) even had an improvement in liver function secondary to the introduction of biotherapy. For the 7 patients receiving infliximab to treat auto-immune hepatitis, 5 patients presented recurrent infections. For patients with NAFLD, no infectious event was reported and an improvement of the hepatic biological parameters was observed, suggesting an improvement in liver function. Conclusions The results of this review suggest that in case of compensated cirrhosis, TNF-blockers were not deleterious for the liver and did not increase the infectious risk. In case of auto-immune cirrhosis, TNF-blockers increased the infectious risk. In case of NAFLD, TNF-blockers might improve liver function and prevent fibrosis. Disclosure of Interest None declared

International audience; Background: Data on infectious endocarditis (IE) in patients with liver cirrhosis (LC) are sparse. We aimed to describe the characteristics and predictors of mortality from IE in patients with LC.Patients and methods: Overall, 101 patients with LC and 101 controls with IE matched for sex, age, date of IE, and diabetes were retrospectively selected in 23 liver units between 2000 and 2013.Results: Mean age was 60.8±10.5 and 60.6±11.5 years in LC and controls, respectively. Causes of cirrhosis (Child-Pugh A/B/C: 10.4%/41.7%/47.9%, MELD score: 17±7.8) were excess alcohol intake (79.6%), viral hepatitis (17.3%), and metabolic syndrome (14.3%). Previous history of cardiopathy was found in 24.8% of LC (prosthetic valve 8.9%) and 37.6% of controls (P=0.07). The most frequent bacteria involved were gram-positive cocci. LC had significantly fewer aminoglycosides (P=0.0007), rifamycin (P=0.03), and valve surgery (P=0.02) than controls. The proportion of patients who died following cardiac surgery was similar between the two groups (9.7% for LC vs. 8.7% for controls, P=1). In-hospital mortality for Child-Pugh C patients was significantly higher than controls (61.4 vs. 23%, P

Background & aims Copeptin is a stable cleavage product of the arginine vasopressin (AVP) precursor and is equimolarly secreted with AVP. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. We aimed to investigate the association between severity of cirrhosis and copeptin concentrations and to confirm whether copeptin is of prognostic significance in cirrhosis. Methods One hundred and eighty-four cirrhotic patients hospitalized in two tertiary referral centres were studied. Serum copeptin was measured in samples obtained at hospital admission. Differences in serum copeptin between Child-Pugh classes were evaluated using the Kruskal-Wallis test. Cox proportional hazard regression and Kaplan-Meier analyses were performed to evaluate associations of copeptin and other possible prognostic factors with 6- and 12-month mortality. Results Median serum copeptin (interquartile range) increased significantly through Child-Pugh classes A [5.4 (3.1-10.7) pmol/L], B [9.6 (6.0-17.3) pmol/L] and C [13.8 (5.8-34.1) pmol/L, P 12.3 pmol/L displayed significantly higher mortality rates at 6 and 12 months as compared to those with serum copeptin ≤12.3 pmol/L (Log-rank test: P 12.3 pmol/L was significantly associated with mortality, particularly at 6 months, independently of age, clinical parameters and Model for End stage Liver Disease (MELD), MELD-sodium and Child-Pugh score. Conclusions Serum copeptin concentration increases significantly along with the severity of cirrhosis as defined by the Child-Pugh classification. A high serum copeptin concentration predicts survival, particularly at 6 months, independently of liver-specific scoring systems in a heterogeneous population of hospitalized cirrhotic patients.

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.

Hormonal factors, like oral contraceptives, create a predisposition to hepatocellular adenoma. We present the case of a young woman with an inflammatory hepatocellular adenoma occurring in the context of a polycystic ovary syndrome. In view of this possible relationship, it would be recommended to follow up patients with hyperandrogenism with repeated liver tests and ultrasonographics. Furthermore, this observation illustrated some difficulties to differentiate remodelled inflammatory hepatocellular adenoma and focal nodular hyperplasia and underlined the interest of immunohistochemical markers for the right diagnosis.

Copeptin, secreted stoichiometrically with vasopressin, demonstrated its prognostic role in various diseases other than cirrhosis.We investigated the association between severity of cirrhosis and plasma concentrations of copeptin, and the prognostic value of copeptin in 95 non-septic cirrhotic patients (34 Child-Pugh A, 29 CP-B, 32 CP-C), 30 septic patients with a Child-Pugh8 ('group D'), and 16 healthy volunteers. Patients were followed for at least 12 months to assess the composite endpoint death/liver transplantation.Median copeptin concentrations (interquartile range) increased through healthy volunteers group [5.95 (3.76-9.43) pmol/L] and 'group D' patients [18.81 (8.96-36.66) pmol/L; P0.001)]. During a median follow-up of 11.0 ± 6.1 months, 28 non-transplanted patients died and eight were transplanted. In receiver operated characteristic curves analysis, the area under the curve values were as follows: Child-Pugh score 0.80 (95% CI: 0.71-0.86), model of end-stage liver disease (MELD) score 0.80 (0.70-0.86), C-reactive protein (CRP) 0.71 (0.60-0.80) and copeptin 0.70 (0.57-0.79). By stratifying the values of these variables into tertiles, the risk of death/liver transplantation for patients belonging to the highest tertile of copeptin (13 pmol/L) was high (Log-rank test: P = 0.0002) and 2.3-fold higher than for patients with lower concentrations after adjusting for MELD score (21) and CRP (24 mg/L) in a Cox model. Other potential predictors (age, total cholesterol, natraemia and serum free cortisol) did not reach a significant level.In cirrhotic patients, copeptin concentrations increased along with the severity of liver disease. In our cohort, the 1-year mortality or liver transplantation was predicted by high MELD score and high concentrations of CRP and copeptin.

Summary Background Guidelines recommend antibiotic prophylaxis (AP) in well-selected groups of cirrhotic patients, but the impact of these recommendations has not been assessed in France. Aim To evaluate AP prescription tendencies for gastrointestinal bleeding, and primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP). Methods Practitioners (n = 1,159) working in general hospitals (GH) or in university hospitals (UH) received a self-administered questionnaire. Results Three hundred and eighty-nine (33.6%; GH 35% and UH 30.4%) practitioners responded. AP was prescribed by 97.7%, 72.3% and 94.8% of practitioners, without significant differences between UH and GH, respectively, for gastrointestinal bleeding (quinolones 48.2%, third-generation cephalosporins 27.7% and amoxicillin-clavulanic acid 22.2%), primary (quinolones 97.2%) and secondary prophylaxis of SBP (quinolones 99%). For gastrointestinal bleeding, ofloxacin (47.6%) and norfloxacin (37.4%) were the main quinolones prescribed, and ceftriaxone (77%) was the main third-generation cephalosporin prescribed. The principal reasons for prescribing AP were a decrease in bacterial infection (88.9% for gastrointestinal bleeding, 91.3% for primary and 94.3% for secondary prophylaxis of SBP), a recommendation by a consensus conference (83%, 38% and 74.4% respectively) and an improvement in survival (72.8%, 41.3% and 57.7% respectively). Only 31.7% of practitioners (39.6% for UH vs. 28.6% for GH; P = 0.038) believed that AP may reduce the risk of bleeding recurrence. Reported side effects (28%) of AP mainly concerned the risk of quinolone resistance (62% of cases). Conclusion Antibiotic prophylaxis is well-recognized by French practitioners, but its routine use depends on the expertise of practitioners. Quinolones remain the main antibiotic class prescribed irrespective of the type of prophylaxis.

Hydrothorax liver is defined by the presence of pleural effusion greater than 500mL secondary to portal hypertension in cirrhotic patients. Poor tolerance of hepatic hydrothorax makes the therapeutic management of these fragile patients and is associated with iatrogenic complications. The mechanism of hydrothorax formation cirrhosis is due to a unidirectional transfer of the abdominal ascites through the diaphragmatic gaps (that were identified macroscopically and microscopically) in the pleural cavity. The treatment of hepatic hydrothorax is determined by the possibility or not of liver transplantation. In some patients, anastomosis portocaval transjugular (TIPS) may however be sufficient.

International audience; BACKGROUND AND AIMS: Bleeding from gastric varices is more severe than that from esophageal varices, but its management remains debated. We aimed to determine how French hepatogastroenterologists manage cirrhotic patients with gastric varices.METHODS: Hepatogastroenterologists (n=1163) working in general or university hospitals received a self-administered questionnaire.RESULTS: Overall, 155 hepatogastroenterologists (13.3%) from 112 centers (33.3%; 39/40 university hospitals, 73/296 general hospitals) answered. Primary prophylaxis was used by 98.1% of hepatogastroenterologists as follows: β-blockers 96.1% (93.8 vs. 97.0%; university vs. general hospitals respectively; P=0.57), glue obliteration 16.9% (17.2 vs. 16.3%; P=0.88), and transjugular intrahepatic portosystemic shunt (TIPS) 8.0% (12.7 vs. 4.6%; P=0.12). To manage bleeding, university hospitals had greater local access to glue obliteration (95.4 vs. 68.2%; PCONCLUSION: The management of gastric varices in France is heterogeneous across centers. University hospitals have better access to techniques such as glue obliteration and TIPS. As bleeding from gastric varices has a poor outcome, guidelines should be established to standardize clinical practices and design further studies.

International audience; OBJECTIVES: We aimed to assess the performance of a new strip (Periscreen) for the rapid diagnosis of spontaneous bacterial peritonitis (SBP). METHODS: Ascitic fluid (AF) of cirrhotic patients hospitalized between March 2014 and August 2015 was independently tested by two readers using the new strip, which has four colorimetric graduations (negative, trace, small, and large). SBP was diagnosed on neutrophils in ascites>250/mm(3). Ascites not related to portal hypertension were excluded. RESULTS: Overall, 649 patients from 21 French centers were included and 1,402 AF (803 AF samples from 315 outpatients and 599 samples from 334 inpatients) were assessed. Eighty-four AF samples (17 AF in 9 outpatients and 67 AF in 31 inpatients) were diagnosed as SBP. The prevalence of SBP was 6% (2.1% in outpatients vs. 11.2% in inpatients; P

Background and Aim: We investigated: (i) the association between severity of cirrhosis and serum levels of free cortisol (SFC) and total cortisol (STC), measured before and 30 min after (T30) the low-dose 1-µg short synacthen test (LD-SST); and (ii) the prognostic value of SFC and STC. Methods: Consecutive, hemodynamically stable, cirrhotic patients (34 Child–Pugh class A, 29B, and 32C) underwent the LD-SST. Patients were followed for at least 12 months to assess non-transplant-related mortality. Results: Child–Pugh class C patients had significantly higher basal levels of SFC than Child–Pugh class A or B patients. Prevalence of suspected adrenal dysfunction ranged between 7.4% (T0 STC

Resume Introduction L’hepatite aigue a VHE devient de plus en plus frequente chez les patients immunodeprimes. Il n’existe pas a l’heure actuelle de recommandation pour la prise en charge de cette infection en cas de traitement immunosuppresseur. Methode Nous rapportons un cas d’hepatite aigue a VHE traitee efficacement par ribavirine chez une patiente suivie pour une polyarthrite rhumatoide (PR) traitee par rituximab. Cas Une femme de 51 ans suivie pour une PR traitee par rituximab a ete hospitalisee pour ictere secondaire a une hepatite aigue a VHE. Elle a ete traitee par ribavirine 800 mg deux fois par jour pendant 2 mois avec une bonne efficacite et tolerance. Finalement trois mois apres l’hepatite aigue a VHE, l’activite de la PR a requis deux nouvelles perfusions de 1000 mg de rituximab. Le traitement a ete bien tolere sans recidive d’hepatite aigue a VHE. Apres un suivi de 8 mois par PCR du VHE dans le sang, il n’a pas ete mis en evidence de recurrence d’hepatite aigue ni d’evolution vers une forme chronique d’hepatite E. Conclusion Ce cas met en lumiere l’efficacite et la surete de la reintroduction du rituximab apres deux mois de traitement par ribavirine et PCR VHE negative.

This population-based study aimed to assess thedeterminants of the outcome of chronic hepatitis C withanalysis of the impact of antiviral therapy with or withoutsustained virological response (SVR) on cirrhosis decom-pensation, hepatocellular carcinoma, liver-related and non-liver-related mortality. A total of 1159 HCV-positive patientsnewly detected between 1994 and 2001 were included. Foreach outcome, the prognostic effect of patients baselinecharacteristics was estimated by time-dependent Cox modelsusing age as the time-scale and adjusting for treatmentreceived during follow-up. The impact of antiviral therapywas assessed by using a propensity score in a sampleincluding 184 patients treated in the first 24 months fol-lowing diagnosis who were matched to 184 untreatedpatients. At the end of a 59-month median follow-up, 100cases of compensated disease, 58 liver cancer and 163deaths (55 liver related) were recorded. The 5-year rates ofdecompensated cirrhosis, hepatocellular carcinoma, liver-related and non-liver-related death were 4.4%, 2.7%, 5.0%and 8.9%, respectively. Multivariate analyses identified twovariables with pejorative influence: alcohol consumption(RR = 4.29 for CD; RR = 5.76 for HCC; RR = 6.69 for liver-related death; P < 0.0001); HCV diagnosis unrelated tosystematic screening (RR = 2.25 for CD; RR = 3.05 forHCC; RR = 4.31 for liver-related death, P < 0.03). In thematched subset, no significant benefit of antiviral therapywas observed. Nevertheless, among the 144 patients whoachieved SVR, no death was observed. This population-basedstudy showed substantial rates of decompensated cirrhosis,hepatocellular carcinoma and non-liver-related mortality.Alcohol consumption and absence of systematic screeningwere significant determinants of poor outcome, whereastreatment did not have significant influence.Keywords: antiviral therapy, hepatitis C, liver-related mor-tality, non-liver-related mortality, outcome, population-based cohort study, survival bias.

Objective: Because over 90% of serum cortisol is bound to albumin and corticosteroid-binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics without altering serum-free and salivary cortisol concentrations. Methods: We assessed basal (T0) and post-synacthen (T60) serum total cortisol, serum-free and salivary cortisol in 125 consecutive cirrhotics (95 non-septic and 30 septic patients with a Child>8). Results: Serum total cortisol levels significantly decreased from the Child A–C non-septic group, as did albumin and CBG levels, with a non-significant rise in serum-free cortisol concentrations. Non-septic patients with low albumin (≤25 g/L) or CBG levels (≤35 mg/L) had lower T0 serum total cortisol levels than patients with near-normal albumin (303.4 vs. 382.6 nmol/L; P=0.0035) or with normal CBG levels (289.9 vs. 441.4 nmol/L; P