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Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period.Pediatric-onset IBD (17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification.1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/10In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD.

We compared the Sanger sequencing and the commercial INNO-LiPA® HBV assay for the routine detection of precore (PC) and basal core promoter (BCP) mutations of hepatitis B virus in chronically infected patients. The overall agreement rate between assays was 94.2% and 98.8% for the detection of PC and BCP mutations, respectively.

In France, the hepatitis B maternal-fetal transmission prevention strategy is based on serovaccination at birth. Serum therapy is to inject 30IU/kg of anti-HBs specific immunoglobulins of human origin in the first hours of life, which in practice corresponds to 1ml or 100IU. Vaccination should also be performed during the first hours of life, and a new injection should be performed at 1month and 6months. In infants less than 32weeks and/or less than 2kg, lower vaccine response leads to prescribe an additional injection at 2months. This serovaccination reduces the risk of mother to child transmission from 57 to 4 %. The failure risk factors of serovaccination are high maternal viral load (greater than or equal to 7 log) and/or the presence of HBeAg. The delivery route does not change the risk of maternal-fetal transmission of hepatitis B when serovaccination at birth was well conducted. Likewise, breastfeeding does not change the risk of maternal-fetal transmission of hepatitis B after serovaccination. It is recommended by WHO. During labor, the pH in utero should be done only when strictly necessary, the published data do not allow to conclude on the risk of transmission.

In France, the prevalence of chronic hepatitis B is about 1% in pregnant women (usually asymptomatic carriers of HBsAg). The risk of maternal-fetal transmission of hepatitis B is particularly high when viral load measured by PCR is higher in mothers (above 7 log) or HBeAg is present. In case of maternal-fetal transmission of hepatitis B, the risk to the newborn of developing subsequent chronic hepatitis B is very high (90%), with long-term complications such as cirrhosis and hepatocellular carcinoma. The prevention of maternal-fetal transmission is based on systematic testing for hepatitis B during pregnancy, followed by serovaccination of the newborn at birth. If necessary, amniocentesis can be realised but will avoid the realization of a transplacental gesture. In case of high viral load, the establishment of a maternal antiviral treatment with lamivudine or tenofovir from 28SA can further reduce the risk of transmission. Given the low resistance it induces, tenofovir should be used preferentially.

Understanding the mechanisms of outcome according to the time frame can help optimize the therapeutic development in severe alcoholic hepatitis. We assessed short-term and long-term survival in severe alcoholic hepatitis based on baseline disease severity, extent of therapeutic improvement, long-term influence of alcohol relapse, and their interaction. Data and alcohol consumption were prospectively recorded in 398 patients treated with corticosteroids in the short term (from corticosteroid initiation to 6 months) and long term (from 6 months to maximum follow-up time). Cumulative incidence rate of first alcohol relapse was 25.2%, 33.7%, and 35.2% at 1, 3, and 5 years, respectively. Alcohol relapse (≥30 g/day) was not associated with mortality (P = 0.24) during the short-term period (1,606 patient-months at risk), but the Lille (P 0.0001) and Model for End-Stage Liver Disease (P 0.0001) scores were independent prognostic factors. In patients who were alive at 6 months (median follow-up, 42 months; interquartile range 11-88), corresponding to 10,413 patient-months at risk, alcohol consumption (≥30 g/day) was associated with mortality (hazard ratio, 3.9; P 0.0001). Additional analysis with abstinent patients as a reference showed a dose effect of alcohol on the hazard ratio of death: 2.36 (P = 0.052) for 1-29 g/day, 3.2 (P = 0.003) for 30-49 g/day, 3.51 (P 0.0001) for 50-99 g/day, and 5.61 (P 0.0001) for ≥ 100 g/day. The baseline Model for End-Stage Liver Disease score was not predictive of long-term outcome, while Lille score (P = 0.02) and alcohol relapse (P 0.0001) were independent prognostic factors.This study shows that new therapeutic development for severe alcoholic hepatitis must target liver injury in the short term and alcohol consumption in the long term; thus, health agencies can endorse future study designs adapted to the time frame of factors influencing mortality; with this in mind, drug-targeting mechanisms involved in liver injury should only be tested for the short-term period. (Hepatology 2017;66:1464-1473).

International audience; In France, the prevalence of chronic hepatitis B is about 1% in pregnant women (usually asymptomatic carriers of HBsAg). The risk of maternal-fetal transmission of hepatitis B is particularly high when viral load measured by PCR is higher in mothers (above 7 log) or HBeAg is present. In case of maternal-fetal transmission of hepatitis B, the risk to the newborn of developing subsequent chronic hepatitis B is very high (90%), with long-term complications such as cirrhosis and hepatocellular carcinoma. The prevention of maternal-fetal transmission is based on systematic testing for hepatitis B during pregnancy, followed by serovaccination of the newborn at birth. If necessary, amniocentesis can be realised but will avoid the realization of a transplacental gesture. In case of high viral load, the establishment of a maternal antiviral treatment with lamivudine or tenofovir from 28 SA can further reduce the risk of transmission. Given the low resistance it induces, tenofovir should be used preferentially.; En France, la prévalence de l’hépatite B chronique est d’environ 1 % chez la femme enceinte (portage généralement asymptomatique de l’AgHBs). Le risque de transmission materno-fœtale de l’hépatite B est d’autant plus élevé que la charge virale mesurée par PCR est plus élevée chez la mère (supérieure à 7 log) ou que l’AgHBe est présent. En cas de transmission materno-fœtale du virus de l’hépatite B, le risque pour le nouveau-né de développer une hépatite B chronique ultérieure est très élevé (90 %), avec des complications à long terme telles que la cirrhose et le carcinome hépatocellulaire. La prévention de la transmission materno-fœtale repose sur le dépistage systématique de l’hépatite B durant la grossesse, suivie de la sérovaccination du nouveau-né à la naissance. En cas de nécessité, l’amniocentèse n’est pas contre-indiquée mais on évitera la réalisation d’un geste transplacentaire. En cas de charge virale supérieure ou égale à 7 log, un traitement antiviral à partir de 28 SA peut encore diminuer ce risque de transmission. En raison du faible risque de résistance virale et de sa bonne tolérance, le ténofovir doit être préféré à la lamivudine.

Background & Aims In severe (Maddrey score ≥32) alcoholic hepatitis (AH), infection is classically viewed as a contraindication for corticosteroids, although specific data are lacking. This study's aims were (1) to evaluate the incidence of infection in patients with severe AH before and after corticosteroid treatment; (2) to determine whether infection contraindicates corticosteroids; and (3) to focus on predictive factors of development of infection. Methods At admission, systematic screening of infection consisted of chest x-ray and blood, ascites, and urinary cultures. All patients were treated with prednisolone. Response to steroids was defined using the Lille model. Results Two hundred forty-six patients with severe AH were prospectively included. Infections at admission were as follows: 63 infections (25.6%) were diagnosed: 28 (44.4%) spontaneous bacterial peritonitis or bacteremia, 8 (12.7%) pulmonary infections, 20 (31.7%) urinary tract infections, and 7 (11.2%) other infections. Patients infected before using corticosteroids had 2-month survival similar to that of others: 70.9% ± 6.1% vs 71.6% ± 3.4%, respectively, P = .99. Development of infection after steroids: 57 patients (23.7%) developed infection: 16 (28.1%) spontaneous bacterial peritonitis or bacteremia, 23 (40.3%) pulmonary, 10 (17.5%) urinary tract, and 8 (14.1%) other infections. Infection occurred more frequently in nonresponders than in responders: 42.5% vs 11.1%, respectively, P P = .0002) independently predicted infection upon steroids use. The Lille model ( P = .000001) and Model for End-Stage Liver Disease score ( P = .006) were independently associated with survival, whereas infection was not ( P = .52). Conclusions Severe AH is associated with high risk of infection. Infection screening is warranted but should not contraindicate steroids. In terms of mechanisms, nonresponse to steroids is the key factor in development of infection and prediction of survival.

In France, the hepatitis B maternal-fetal transmission prevention strategy is based on serovaccination at birth. Serum therapy is to inject 30IU/kg of anti-HBs specific immunoglobulins of human origin in the first hours of life, which in practice corresponds to 1ml or 100IU. Vaccination should also be performed during the first hours of life, and a new injection should be performed at 1month and 6months. In infants less than 32weeks and/or less than 2kg, lower vaccine response leads to prescribe an additional injection at 2months. This serovaccination reduces the risk of mother to child transmission from 57 to 4 %. The failure risk factors of serovaccination are high maternal viral load (greater than or equal to 7 log) and/or the presence of HBeAg. The delivery route does not change the risk of maternal-fetal transmission of hepatitis B when serovaccination at birth was well conducted. Likewise, breastfeeding does not change the risk of maternal-fetal transmission of hepatitis B after serovaccination. It is recommended by WHO. During labor, the pH in utero should be done only when strictly necessary, the published data do not allow to conclude on the risk of transmission.

Resume L’infection par le virus de l’hepatite C (VHC) a une prevalence evaluee a 1,2 % de la population francaise dont 80 % sont porteurs chroniques du virus, avec comme principale complication d’un tel etat la survenue d’une cirrhose dans 15 a 20 % des cas dans un delai moyen de 15 a 20 ans. L’association de l’interferon α (IFNα) a la ribavirine est actuellement le traitement de reference de l’hepatite chronique C. Le benefice therapeutique se fait au prix de nombreux effets indesirables lies classiquement a l’IFNα. En particulier, les troubles thymiques representent la cause la plus frequente de diminution (et d’arret) de traitement. Nous nous proposons dans cet article d’exposer : 1) les elements de discussion sur la question de l’imputabilite des troubles thymiques induits par l’IFNα lors du traitement de l’hepatite C chronique ; 2) les differentes hypotheses elaborees pour eclairer leur physiopathologie. Imputabilite des troubles thymiques a l’IFNα : les principales sources d’equivoque en matiere d’imputabilite de la depression a l’IFNα sont, d’une part, que l’infection par le VHC s’accompagne d’une prevalence accrue de la depression, et ceci en dehors de tout traitement antiviral et que, d’autre part, le taux de contamination dans les populations psychiatriques est plus eleve que dans la population generale. Ce dernier point est comprehensible aisement pour les usagers de drogues par voie veineuse mais est plus inattendu en cas de d’abus ou de dependance d’alcool, d’atteinte alcoolique hepatique, d’hospitalisation pour retard mental, psychose ou demence, ou de psychotraumatisme. Malgre ces elements confondants, l’imputabilite de troubles thymiques a l’IFNα lui-meme repose sur des donnees nombreuses et variees. Tout d’abord, l’IFNα appartient a une famille de molecules, les cytokines, qui sont tenues pour responsables de la plupart des symptomes physiques et psychiques lies a l’infection et l’inflammation. Ensuite, de nombreuses equipes ont rapporte la survenue de manifestations psycho-comportementales chronologiquement consecutives au traitement IFNα : labilite emotionnelle (11 %), anxiete (14 %), irritabilite (32 %), difficultes de concentration (18 %), troubles du sommeil (37 %) et depression (34 %), idees suicidaires (1,2 %), passages a l’acte suicidaires et troubles psychotiques aigus (episodes delirants hallucinatoires ou interpretatifs sur terrain predispose). La frequence des troubles thymiques est tres variable, allant de 0 a 37 %. Cette variabilite peut etre expliquee par l’heterogeneite : 1) des posologies et des durees de traitements par interferon, 2) des populations de patients acceptes dans les protocoles therapeutiques, notamment des criteres d’exclusion relatifs a l’etat psychiatrique ou a l’abus de substances, et 3) des methodes d’evaluation de la depression. Physiopathologie : tout d’abord, la nature des symptomes psycho-comportementaux peut etre discutee, certains auteurs voyant dans certains d’entre eux (baisse de l’humeur, deficit mnesique, ralentissement cognitif et alteration des fonctions executives) les stigmates d’une legere demence frontale sous-corticale, telle qu’on peut en rencontrer dans des affections neurologiques (maladie de Parkinson, par exemple). Cette hypothese est appuyee par certains travaux mettant en evidence des signes d’encephalopathie a minima. Par ailleurs, les effets comportementaux de l’IFNα ont ete relies a d’autres mecanismes tels que la douleur, la liberation d’opioides centraux ou le stress aigu. Cependant, la nature thymique des troubles induits par l’IFNα demeure la plus largement admise dans la litterature. Dans ce cadre, l’etude de la physiopathologie des troubles s’avere relativement complexe et aboutit a des conclusions questionnant les theories classiques de la depression. Dans une perspective dynamiste de la maladie, le trouble depressif majeur est alors vu comme la consequence d’une reponse comportementale inappropriee vis-a-vis d’un etat de « malaise », lui-meme engendre par une activation immunitaire incluant des anomalies du systeme des cytokines. L’induction de troubles thymiques sous IFNα serait un exemple particulier de ce mecanisme. Quoi qu’il en soit, il est a noter que l’IFNα exogene utilise en therapie est un polypeptide qui ne passe pas la barriere hemomeningee saine. Il est donc necessaire d’envisager la possibilite d’un mecanisme peripherique intermediaire: activation d’une cascade de production d’autres cytokines endogenes capables d’une action centrale, ou d’une enzyme hepatique impliquee dans le metabolisme de precurseurs de la serotonine, neuromediateur majeur dans les theories monoaminergiques de la depression. Il a ainsi ete montre que le traitement par IFNα provoque une modification des taux seriques de tryptophane, acide amine precurseur de la serotonine, une diminution des taux du principal metabolite de la serotonine (le 5-HIAA) dans le LCR et une alteration des recepteurs serotoninergiques centraux. De plus, les antidepresseurs inhibiteurs selectifs du transporteur de la serotonine sont actifs pour traiter ou prevenir l’apparition de depression sous IFNα. Dans une etude recente, les variations des concentrations de tryptophane, de serotonine et de kinurenines (voie accessoire de catabolisme du tryptophane) ont ete correlees significativement aux scores obtenus a l’echelle depression MADRS. En ce qui concerne les autres systemes monoaminergiques, l’IFNα semble avoir un effet amphetamine-like transitoire suivi d’une diminution du tonus dopaminergique en administration chronique. L’IFNα entraine egalement des modifications du systeme noradrenergique. Enfin, des hypotheses neuroendocriniennes ont ete formulees. Conclusion – La conduite a tenir devant les troubles thymiques sous IFNα doit prendre en compte 3 ordres de faits : une relative dose-dependance, une sensibilite satisfaisante aux ISRS, et ses relations possibles avec la symptomatologie physique. Il est ainsi possible de prevenir ou traiter les troubles thymiques en se basant sur ces elements : baisse des posologies, fenetres therapeutiques, prescription d’ISRS, attention particuliere aux symptomes physiques et systematisation de leur traitement preventif. Par ailleurs, dans une perspective de sante publique, ceci devrait contribuer a achever de convaincre les cliniciens de la legitimite de pas ecarter les patients dits « a risque » mais de les manager de facon pragmatique et prudente.

In the present study we report, as part of a large multiple sclerosis (MS) cohort (1800 patients), three cases of untreated patients who developed autoimmune hepatitis (AIH). The prevalence of AIH in the general population is about 0.0169% and seems to be higher in our MS cohort (0.17%). We suggest that a liver biopsy should systematically be performed in untreated MS patients with a sustained increase of liver enzyme.

Background: Monoclonal CD4 antibodies have been proposed as a new immunosuppressant drug in the treatment of inflammatory bowel disease. We report our experience of treatment with a monoclonal anti-CD4 (B-F5) antibody in severe refractory Crohn's disease. Methods: Twelve patients with severe refractory Crohn's disease were treated in an open clinical trial. B-F5 was given intravenously at a dose of 0.5 mg.day/kg for 7 consecutive days (patients 1–8). For patients 9–12, B-F5 was given at a dose of 0.5 mg.day/kg on the first day (day 0) and of 1 mg.day/kg on days 1–6. Follow-up examinations were carried out at days 8, 15, 22 and 30. Endoscopic evaluation was performed on days 0 and 30 in eight of 12 patients. Results: Immediately after the first infusion, one patient had dyspnoea and tachycardia requiring cessation of the treatment. Among the 11 patients who received the complete course of treatment, two had prolonged clinical improvement and two had partial clinical improvement. Significant endoscopic improvement was observed in only one patient. No sustained depletion of CD4+ cells could be observed. Conclusion: In this uncontrolled open trial, monoclonal anti-CD4 B-F5 antibody was not successful in severe Crohn's disease.

Resume Ces dernieres annees, differents virus ont ete incrimines dans l'etiopathogenie du syndrome de Gougerot-Sjogren (SGS) primitif et plus particulierement le virus de l'hepatite C. Nous avons mene une etude prospective portant sur 23 patients presentant un SGS, a la recherche de signe d'infection par le virus de l'hepatite C. et sur 23 patients presentant une hepatite chronique active C, a la recherche d'un SGS primitif. La prevalence du virus C dans le groupe de Sjogren est de 4,7 %, ce qui n'est pas significativemenl plus eleve que notre population temoin. Parallelement la recherche d'un SGS primitif dans le groupe hepatite chronique C met en evidence quatre patients (sexe feminin, âge moyen: 48.5 ans) dont le tableau clinique est compatible avec ce diagnostic. Il n'est retrouve d'anticorps antinucleaires chez aucun de ces 23 patients. Le typage lymphocytaire de l'infiltrat sur les biopsies des glandes salivaires accessoires a mis en evidence une predominance des lymphocytes CD8 dans un rapport de 2/1 a l'inverse de ce qui est habituellement retrouve dans le SGS primitif. Au terme de cette etude, le virus de l'hepatite C parait etre plus a l'origine d'une sialadenite chronique lymphocytaire que d'un authentique SGS.

International audience; Importance Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown.Objective To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone.Design, Setting, and Participants Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome.Intervention Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days.Main Outcomes and Measures Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment.Results In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07).Conclusion and Relevance In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline.Trial Registration clinicaltrials.gov Identifier: NCT01214226.

The proinflammatory cytokine interferon (IFN) alpha is commonly used in the treatment of patients with hepatitis C but its administration is often responsible for neuropsychiatric side effects (low mood, fatigue, sleep-wake disorders, irritability and weight loss). Various mechanisms have been incriminated to explain the production of depression and anxiety symptoms, among which serotonergic hypothesis is supported by a growing body of evidence. The latter posits that IFN-alpha is responsible for central serotonin (5-HT) depletion by deviating its precursor, tryptophan (TRP), to a catabolic kynurenine (KYN) pathway through induction of indoleamine 2.3 dioxygenase (IDO). The aim of the study was to examine the time variation of 5-HT blood (serum and platelet) levels and serum KYN/TRP ratio along with instauration of IFN-alpha therapy and to correlate these biological variations with mood fluctuations.Patients. Ten patients (mean [S.D.] age 45 years [12.7], range 29-63; three males, seven females) with chronic hepatitis C eligible to receive IFN-alpha (1.5microg/kg/week Viraferon, Schering-Plough, administered subcutaneously) were recruited from the Gastroenterology department of the University hospital of Lille, France. Patients with cirrhosis, HIV or hepatitis B or D co-infection, persistent intravenous addiction, corticoid therapy or any DSM-IV axis 1 psychiatric disorder (diagnosed with MINI interview) were excluded. Patients with chronic active hepatitis C were assessed at baseline and monthly during the first semester of IFN-alpha and ribavirine bi-therapy. Measurements. The Montgomery Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) were used to assess depression and anxiety fluctuations. Serum and platelet serotonin levels were determined by HPLC with coulometric detection. Simultaneous quantification of TRP and KYN was determined by means of HPLC with fluorescence detection (TRP) or UV detection (KYN). Statistics. TRP, KYN concentrations and KYN/TRP ratio as well as MADRS and HAM-A measurements were performed at three time points (day 1, weeks 4 and 12) of IFN-alpha therapy. Analysis of variance used a linear model (with subject as the random factor) and correlation between measurements used an autoregressive model of order 1. For all probabilities, the level of significance was set at P.05.Two patients were excluded before the first post-treatment assessment (results not shown). In the eight remaining patients, we observed significant increase of KYN/TRP ratio from baseline to early (week 4) and late (week 12) assessments (respectively, mean [S.D.] 5.57[5.24], 13.52[15.53] and 29.78[14.11], with P=.04). Similarly, significant increase in the MADRS (respectively 7.13[5.2], 12[6.9] and 16.6[8.6], with P=.03) and HAM-A (respectively 9.25[6.27], 15.1[6.95] and 18.7[6.27], with P=.02) mean scores were observed. Serum and platelet serotonin levels showed no significant variation with time.The results are consistent with the physiopathological hypothesis of an induction of IDO underlying depressive and anxiety symptoms related to IFN-alpha therapy in patients with chronic active hepatitis C. Nevertheless, this pilot study allows no firm conclusion since sample effective is weak and delay between IFN-alpha weekly injection and psychiatric and biological assessment was not controlled and thus may have biased our findings. However, these encouraging results advocate for further exploration of tryptophan metabolism for a better understanding of individual vulnerability to IFN-alpha-induced psychiatric adverse effects.

Aims: In response to the opioid overdose epidemic, a safety net hospital implemented a policy to ensure emergency department (ED) patients at risk for opioid overdose are offered naloxone rescue kits (NRKs). Study aims are to: (1) determine the extent of implementation, (2) describe barriers and facilitators to adoption. Methods: Mixed methods for formative evaluation: electronic medical record (EMR) query to identify patients at risk and rate of NRK provision, and qualitative interviews with diverse ED staff analyzed via grounded theory to identify barriers and facilitators. Results: The policy supports 3 methods of NRK provision: (1) distribution by Licensed Alcohol and Drug Counselors (LADCs), (2) outpatient pharmacy prescriptions, (3) inpatient pharmacy distribution by ED staff (when LADCs unavailable). In the first 7 months, 1241 ED patients were at risk; of these 12% (n=150) received NRK (142 via LADCs, 5 outpatient prescriptions, 3 ED staff). Interview results indicate support for policy and implementation barriers. Patient barriers: population often not receptive to NRK, not accompanied toEDbyasupportiveother. Staff barriers:unfamiliaritywith policy, lack of clarity regarding responsibility for distribution, lack of consensus on patients appropriate. Process barriers: method of obtaining kit unclear, confusion around standing verbal order, not integrated into EMR. Staff suggestions to improve uptake include: simplifying process, targeted training, role clarification, integration into EMR. Conclusions: ED staff support provision of NRKs andmany barriers aremodifiable. Findingsmay have applications for integrating the intervention into other ED settings. Financial support: Boston University School of Public Health Pilot Grant Program.

International audience; BACKGROUND & AIMS: Several models have been used to determine prognoses of patients with alcoholic hepatitis. These include static systems (the Maddrey discriminant function; age, bilirubin, international normalized ratio, creatinine [ABIC] score; and model for end-stage liver disease [MELD] score) and dynamic models (the Lille model). We aimed to combine features of all of these models to develop a better method to predict outcomes of patients with alcoholic hepatitis.METHODS: We collected data from several databases of patients with severe alcoholic hepatitis treated with corticosteroids in France and the United Kingdom to create a model to predict patient survival (derivation cohort, n = 538 patients). We compared the performances of 3 joint-effect models (Maddrey+Lille, MELD+Lille, and ABIC+Lille) to determine which combination had the best prognostic value, based on known patient outcomes. The model was validated using data from trials of the effects of corticosteroids in patients in the United States, France, Korea, and Belgium (n = 604 patients).RESULTS: We created a joint-effect model to predict patient survival after 2 and 6 months; in the derivation and validation cohorts it predicted outcome significantly better than either static or dynamic models alone (P < .01 for all comparisons). The joint model accurately predicted patient survival regardless of patient risk level. The MELD+Lille combination was better than the Maddrey+Lille or ABIC+Lille combination in predicting patient survival, with Akaike information criterion values of 1305, 1313, and 1312, respectively. For example, based on the MELD+Lille combination model, the predicted 6-month mortality of complete responders with MELD scores of 15-45 (Lille score, 0.16) was 8.5% to 49.7%, compared with 16.4%-75.2% for nonresponders (Lille score, 0.45). According to the joint-effect model, for 2 patients with the same baseline MELD score of 21, the patient with a Lille score of 0.45 had a 1.9-fold higher risk of death than the patient with a Lille score of 0.16 (23.7% vs 12.5%).CONCLUSIONS: By combining results from static and dynamic scoring systems for liver disease, we can better predict outcomes of patients with alcoholic hepatitis, compared with either model alone. This may help patient management and design of clinical trials.

Imputability of thymic disorders caused by IFNalpha during the chronic Hepatitis C treatment -- hepatitis C and depression -- the infection by the hepatitis C virus (HCV) is a major public health concern since it affects 1.2% in the French population. Eighty percent of those contaminated by HCV keep bearing the virus chronically although they remain asymptomatic during many years. HCV infection is associated with psychiatric symptoms like depression. Together with other factors (eg the severity of hepatic condition), depression may induce significant impairment in quality of life. Conversely, some psychiatric conditions may increase the risk of HCV infection. In drug-addicted subjects using intravenous route, HCV contamination rate ranges from 74 to 100%. Compared with general population, a higher HCV contamination rate has also been noticed in some other subgroups of subjects (patients with alcohol abuse or dependence, with alcohol-induced hepatic disease and psychiatric inpatients). However, no valid explanation to this phenomenon has been established. Interferon alpha and depression - Interferons are a variety of cytokines naturally produced by human tissues and have also been synthesized for therapeutic purposes (treatment of a variety of cancers and viral infections). Many psychobehavioural symptoms are observed under IFNalpha treatment. Among them, mood disorders are known to occur early after entry into treatment and to be within the reach of preventive measures. The reported frequency of depression during IFNalpha treatment ranges from 0 to 37%. This variation reflects either methodological biases (eg differences in psychiatric assessment) or the heterogeneity of the population of patients accepted in therapeutic protocols. Note that the adjunction of ribavirine to IFNalpha in therapeutic protocols has not brought any changes in the depression frequency. The causal relationship between IFNalpha administration and the occurrence of mood disorders has been tackled by various recent research works focusing on the importance of the immune system in the pathophysiology of depression. Miscellaneous pathophysiological hypotheses -- nature of the psychobehavioural symptomatology -- in addition to depressive symptoms, IFNalpha treatment also induces various cognitive impairments and disruptions in EEG patterns. These symptoms are consistent with a mild subcortical dementia. Data resulting from pharmacological trials in humans and in animals are controversial (eg IFNalpha-induced symptoms being alleviated by both immune and antidepressant therapies). However, the debate about the nature of the psychobehavioural disorders observed under IFNalpha treatment might be no longer relevant in the light of recent theories which regard depression as a maladaptive response to a particular form of stress, namely a deep and diffuse feeling of sickness ("malaise"). These theoretical views ascribe the production of depressive symptoms to a disruption in the immune function, mediated by the variety of cytokines. The therapeutic effects of anti-depressive drugs are thus attributed to their analgesic properties, reducing the "malaise" feeling underlying depressive symptoms. Necessity of a second messanger -- accordingly to current pathophysiological theories, depression results from disorders of various CNS functions, mainly limbic, monaminergic and neuroendocrinal systems. Though, exogenous IFNalpha does not cross the blood-brain barrier when unscathed and an intermediary mechanism is necessary. First to be addressed is the cytokines system itself since it is composed of numerous different molecules interacting in an infinite number of possible combinations. Some of these cytokines (eg some interleukins) both are activated by IFNalpha and can reach CNS; they are good candidates for the role of second messenger mediating the induction of psychobehavioural disorders. Second, keeping in mind that serotonin is a monoaminergic neurotransmitter classically involved in depression pathophysiology, other works have demonstrated that IFNalpha modulates the peripheral activity of indolamine-dioxygenase -- a regulating enzyme of serotonin metabolism -- possibly through lymphocyte T CD4 activation. Third, other authors have postulated an immune-induced vagal mechanism to explain depression caused by IFNalpha. Action of IFNalpha on the neuroendocrine and on neuromodulating functions: monoaminergic hypothesis -- cytokines could have an influence on the mood through their modulating role on the serotoninergic system. IFNalpha treatment is reported to produce: 1) a decrease in tryptophan availability for serotonin synthesis, 2) a decrease in the 5-HIAA level in the LCR, and 3) a modification of the central serotoninergic receptors. Moreover, selective inhibitors of serotonin transporters are effective to treat or prevent depression caused by IFNalpha. Many studies support the serotonin-transporter hypothesis: in vitro, both IFNalpha and interleukine 4 (IL-4) increases the expression of serotonin transporter gene, IFNalpha increases in the production of IL-4 by mononucleus cells (not found in vivo). Serotoninergic system can also be altered by a peripheral action of IFNalpha on trytophan catabolism by activating a concurrent pathway (known as "kynurenine pathway") to serotonin synthesis. Finally, serotonin-mediated vulnerability to the psychobehavioural effects of IFNalpha could be underlain by a polymorphism of serotonin transporter gene. Concerning the other monoaminergic systems, IFNalpha seems to have an amphetamine-like effect at its first administration, followed by a decrease in dopaminergic tone with chronic administration. Dopaminergic depletion, subsequent to psychostimulant abuse for instance, results in severe depressive syndromes. Interactions between IFNalpha and noradrenergic system have also been reported. Neuroendocrinian hypothesis -- when administered through central or peripheral way, IFNalpha simulates/inhibits the corticotrope axis and alters endorphin system as shown by the induction of analgesia, catatonia and behavioural slowdown that can be suppressed by opioid antagonists. IFNalpha neurotoxic effects are successfully treated by naltrexone. Lastly, IFNalpha is known to cause disorders in thyroid function that are likely to contribute to the production or aggravation of mood disorders.A better understanding of pathophysiologic mechanisms underlying psychiatric side-effects of IFNalpha is essential to extend access to treatment to some categories of patients that remain excluded from the protocols. A better management of those psychiatric side effects should help the clinician not to draw aside patients at risk, ie patients with depression, drug and alcohol addiction. Treating them in a pragmatic and careful way is a major issue, since this population represents a high percentage of the potential candidates for interferon therapy.

To evaluate adjuvant modalities after curative resection for hepatocellular carcinoma using a meta-analysis of randomized and non-randomized controlled trials.In a first step, a meta-analysis of randomized controlled trials was carried out. Sensitivity analyses after inclusion of non-randomized controlled trials were performed. Four therapeutic modalities were evaluated: pre-operative transarterial chemotherapy, post-operative transarterial chemotherapy, systemic chemotherapy and a combination of systemic and transarterial chemotherapy.Only post-operative transarterial chemotherapy improved survival significantly at 2 years [difference, 22.8%; confidence interval (CI), 8.6-36.9%; P = 0.002] and 3 years (difference, 27.6%; CI, 8.2-47.1%; P = 0.005), and decreased the probability of no recurrence at 1 year (difference, 28.8%; CI, 16.7-40.8%; P0.001), 2 years (difference, 27.6%; CI, 8.2-47.1%; P = 0.005) and 3 years (difference, 28%; CI, 8.2-47.9%; P = 0.006). In a sensitivity analysis after inclusion of non-randomized controlled trials, post-operative transarterial chemotherapy still improved survival at 1 year (difference, 9.6%; CI, 0.8-18.3%; P = 0.03), 2 years (difference, 13.5%; CI, 0.9-26%, P = 0.04) and 3 years (difference, 18%; CI, 7-28.9%; P0.001), and decreased the probability of no recurrence at 1 year (difference, 20.3%; CI, 7.7-33%; P = 0.002), 2 years (difference, 35%; CI, 21.4-46.3%; P0.001) and 3 years (difference, 34.5%; CI, 18.7-50.3%; P0.001).Post-operative transarterial chemotherapy improved survival and decreased the cumulative probability of no recurrence. New randomized controlled trials evaluating this modality are required.

Alpha1-antitrypsin (alpha1AT) deficiency is an autosomal recessive disorder that can cause pulmonary emphysema and liver disease. We report here the case of a 59-year-old woman who was admitted to hospital for evaluation of jaundice. She had no history of hepatitis or childhood liver disease. She had never received a blood transfusion, nor had she abused drugs or alcohol. Transjugular liver biopsy was then performed and revealed a micronodular cirrhosis. Ten months later, because of persistent liver cell failure and ascites, she underwent an orthotopic liver transplantation. Investigation of alpha1AT system in the proband revealed a substantial decrease in serum alpha1AT associated with a low elastase inhibitory capacity. The Pi phenotype revealed a PiM-like profile. Sequencing of exons 1-5 demonstrated the presence of the M3 allele. Moreover, a triple nucleotide deletion was detected in exon 2 of one allele. This caused an "in-phase" frameshift, coding for a protein deficient in a single Phe residue, which corresponded to the Mmalton variant. After liver biopsy, periodic acid-Schiff-positive acidophilic bodies resistant to diastase digestion were observed in the cytoplasm of hepatocytes. These results demonstrated that our patient had a heterozygous M3Mmalton alpha1AT genotype related to a deficiency phenotype. This observation is the first of a patient with heterozygous Mmalton genotype associated with an alpha1AT deficiency that induced severe liver disease requiring orthotopic liver transplantation.

Beta-blockers have been shown to reduce portal pressure in patients with cirrhosis and limit the development of portosystemic shunts in portal hypertensive animals. Thus, a randomized double-blind trial was conducted to evaluate propranolol in the prevention of the development of large oesophageal varices in patients with cirrhosis without varices or with small varices.One hundred and two patients received long-acting propranolol (160 mg/day) and 104 patients received a placebo. At inclusion, there was no significant difference between the two groups in terms of clinical characteristics or biochemical tests. At 2 years, the size of varices was estimated on video recordings.One-third of the patients were lost to follow-up, and 95%/97% of the remaining patients were compliant in the propranolol and placebo groups, respectively. At 2 years, the proportion of patients with large varices was 31% in the propranolol group and 14% in the placebo group (P0.05). Three and four patients bled in the propranolol and placebo groups, respectively, and nine and ten died, respectively.This trial suggests that propranolol administration cannot be recommended for the prevention of the development of large oesophageal varices in patients with cirrhosis; thus other studies are needed in selected subgroups of patients.

To determine the diagnostic value of systematic liver needle biopsy and endoscopic retrograde cholangiography in patients with unexplained chronic anicteric cholestasis.Seventy nine patients presented with anicteric cholestasis for over 6 months as defined by: a concomitant increase in at least 2 of 3 cholestatic enzymes (GGT, alkaline phosphatase, 5'nucleotidase); a low cytolytic ratio (ALT/AP (xN/xN)or = 5); and negative test results (normal ultrasound scan; no antimitochondrial antibodies, viral, drug-induced, or toxic hepatitis, or known ulcerative cholitis). Based on liver biopsy and endoscopic retrograde cholangiography, 5 groups were determined; group A: normal liver biopsy and endoscopic retrograde cholangiography; group B: primary sclerosing cholangitis with histological biliary lesions; group C: primary sclerosing cholangitis with normal histology; group D: histologic biliary lesions alone; group E: other (aspecific histologic lesions, isolated anomalies of intrahepatic bile ducts on endoscopic retrograde cholangiography).Diagnosis of cholestasis was fortuitous in 43% of cases. Group A: 5 patients had normal liver biopsy and endoscopic retrograde cholangiography; group B (10 patients): 5 with destructive cholangitis, 5 with degenerative cholangitis, associated with portal fibrosis in 90%; group C: none of the patients had primary sclerosing cholangitis with normal histology; group D: 39 patients {idiopathic ductopenia (1), Caroli's disease (1), benign recurrent cholestasis (1), regenerative nodular hyperplasia (4), destructive cholangitis without ductopenia (7), degenerative cholangitis (15), ductular proliferation (10)}; group E: 24 patients with aspecific histologic lesions, and one patient with isolated anomalies of the intrahepatic bile ducts on endoscopic retrograde cholangiography.In the present population: a) 13% presented with intense cholangitis and primary sclerosing cholangitis on endoscopic retrograde cholangiography; b) 49% presented with various histologic biliary lesions without primary sclerosing cholangitis. We conclude that in chronic anicteric cholestasis of unexplained origin, first choice work-up should include liver biopsy, and endoscopic retrograde cholangiography should only be performed when intense histologic cholangitis is observed.

The aim of this study was to assess the sensitivity of MR imaging in the diagnosis of liver hemochromatosis and its ability to quantify hepatic iron concentration (HIC).MR images were prospectively obtained in 58 patients suspected to have hemochromatosis. We used a scanner with a 0.5-T magnet and two sequences: gradient-echo T1-weighted (400/12 [TR/TE], 90 degrees flip angle) and gradient-echo T2*-weighted (700/30, 30 degrees flip angle) sequences. Measurement of the liver-to-muscle signal-intensity ratio was compared with the HIC value measured at biopsy for each patient.Both MR sequences showed significant correlation between decreased signal-intensity ratios and increased HIC (r = -.87 for T1-weighted sequences and r = -.74 for T2*-weighted sequences). The sensitivity and specificity of the T2*-weighted sequence (signal-intensity ratio0.8) to detect iron overload (HIC36 mumol/g) were 91% and 88%, respectively. The best correlation was obtained with T2*-weighted sequences, when patients had an HIC less than 100 mumol/g (r = -.71); with T1-weighted sequences, the best correlation was obtained when patients had an HIC of 100-324 mumol/g (r = -.67). We found a significant correlation between the HIC revealed on MR images, calculated from both sequences, and that measured at biopsy when patients had an HIC of less than 300 mumol/g (r = -.93, p.01).MR imaging shows promise in differentiating normal from abnormal hepatic iron concentration and in grossly quantifying moderate degrees of hepatic iron overload.

We report 7 pregnancies which occurred from 1988 to 1995 in 5 women who underwent liver transplantation. The immunosuppression regimen associated cyclosporine, azathioprine and prednisone.Mean age at conception was 25. During pregnancy, cholestasis occurred in 2 women. None of the patients experienced rejection. An increase in serum creatinine was observed in 3 cases. Serum uric acid increased in the third trimester of pregnancy in 6 cases, associated with arterial hypertension in 3 cases. In 4 cases, toxemia led to premature delivery. Seven childbirths occurred between the 34th and 38th week of gestation, by vaginal delivery (n = 3) or caesarean section (n = 4). Newborn weights ranged from 1,350 g to 3,100 g. A favorable outcome was observed in all mothers, with a follow-up ranging from 2 months to 7 years after delivery.These results suggest that a successful pregnancy is possible after liver transplantation in young women with normal hepatic function and treated with cyclosporine. The risk of toxemia is mainly related to renal function before pregnancy.

These last years, different virus have been incriminated in the etiopathogeny of the primary-Sjögren's syndrome and more particularly the hepatitis C virus. We have led a prospective study over 23 patients presenting a primary Sjögren's syndrome, searching for a sign of infection by the hepatitis C virus and over 23 patients presenting an active chronic hepatitis C virus searching for a Gougerot-Sjögren syndrome. The overcoming of the hepatitis C virus in the Sjögren group was 4.7% which was not significatively higher than in our sample of population. Parallelly, the search of the Sjögren's syndrome, in the hepatitis C virus group, found 4 patients (feminine, average age 48.5 years old) whose clinical board was compatible with this diagnostic. Antinuclear antibodies have not been found in any of the 23 patients. The lymphocytic typing of the infiltrate in the minor salivary glands biopsies showed a predominance of the CD8 lymphocytes in a proportion of 2/1, contrasting with what is observed in primary Sjögren's syndrome. We concluded that hepatitis C virus may be more associated with a chronic lymphocytic sialadenitis than an authentic primary Sjögren's syndrome.

100 BASELINE MODELS HELP IN IDENTIFYING RESPONDERS TO CORTICOSTEROIDS IN SEVERE ALCOHOLIC HEPATITIS: A MULTICENTER STUDY ON MORE THAN 600 PATIENTS A. Louvet, F. Artru, M. Colin, G. Lassailly, E. Diaz, J.G. O’Grady, J. Boursier, R.L. Carithers, S. Naveau, P. Deltenre, V. Canva-Delcambre, S. Dharancy, T.R. Morgan, P. Mathurin. Maladies de l’Appareil Digestif, Hopital Huriez, Unite 995, INSERM, Lille, Service d’Hepato-Gastroenterologie, Hopital Germon et Gauthier, Bethune, France; Liver Unit, King’s College Hospital, London, UK; Service d’Hepato-Gastroenterologie, CHU, Angers, France; Department of Medicine, Puget Medical Center, Seattle, WA, USA; Service d’Hepato-Gastroenterologie, Hopital Antoine Beclere, Clamart, France; Service d’Hepato-Gastroenterologie, Hopital de Jolimont, Haine-Saint-Paul, Belgium; Veterans Administration Healthcare System, Long Beach, CA, USA E-mail: alexandre.louvet@chru-lille.fr

Introduction L’hemochromatose est une maladie le plus souvent autosomique recessive, dont il existe 6 sous-types. Le plus frequent correspond aux mutations du gene HFE1. Le type 2 est lie aux mutations du gene de l’hemojuveline (HVN) responsable de l’hemochromatose juvenile, forme beaucoup plus severe et precoce souvent revelee par un hypogonadisme hypogonadotrope et cardiopathie. Cas Clinique Nous rapportons le cas d’un patient de 28 ans consultant pour anejaculation recente, menant au diagnostic d’hypogonadisme clinique avec testicules de taille normale, d’origine gonadotrope (Testosteronemie : 0,22 ng/ml (2,5-11), LH : 0,8 UI/l ; FSH : 0,4 UI/l). Le reste de l’hypophysiogramme, l’IRM hypophysaire et le caryotype sont normaux. Un traitement par heptylate de testosterone est debute permettant une virilisation. En raison d’un desir de paternite avec azoospermie, un relais par gonadotrophines est assure. Le patient presente alors une decompensation cardiaque globale severe avec troubles du rythme, liee a une cardiomyopathie dilatee hypokinetique avec fraction d’ejection a 20 % et coronaires saines. La ferritine est a 2 680 ng/ml (n Discussion Le patient souhaite une supplementation androgenique. Or, le carcinome hepatocellulaire est favorise par la surcharge en fer et les steroides sexuels. L’hypoandrogenie expose egalement a des complications (osteoporose…). La question est donc celle du rapport benefice-risque chez cet homme jeune. Conclusion Il faut penser a une hemochromatose juvenile devant un hypogonadisme hypogonadotrope chez un sujet jeune, et ce d’autant plus qu’il existe une cardiopathie. La litterature recente souleve la question du risque carcinogene de l’androgenotherapie compte tenu de l’atteinte hepatique (Gastroenterology 2008). Desir de ≪ sur ≫ vie et symptomes d’hypoandrogenie nous incitent a proposer ce traitement sous stricte surveillance hepatique.