[Wilson's disease]

http://www.huveaux.fr/fr_santesite.aspWilson's disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene chromosome 13. The discovery of the gene allowed a better understanding of cytosolic copper trafficking its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This disease can be efficiently treated by chelation and zinc therapy. Liver transplantation is the therapy to patients with hepatic fulminant course, or in those with relentless progression of hepatic dysfunction in spite of medical therapy

Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma

International audienceBackground: Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC. Methods: 53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics. Results: The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence. Conclusion: This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experience

Background & Aims: Protease inhibitors (PI) with peginterferon/ ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n = 18) or telaprevir (n = 19). The indication for therapy was HCV recurrence (fibrosis stage PF2 (n = 31, 83%) or fibrosing cholestatic hepatitis (n = 6, 16%). Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p = 0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p = 0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p = 0.24). Treatment was discontinued in sixteen patients (treatment failures (n = 11), adverse events (n = 5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n = 34, 92%), treated with erythropoietin and/ or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8 ± 18.2-fold with telaprevir. Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study

peer reviewedBackground: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI –∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8–27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI −0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17–0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33–2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16–0·47] and 0·21 [0·13–0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health—Programme Hospitalier de Recherche Clinique 2010

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SCOPUS: le.jinfo:eu-repo/semantics/publishe

Le consentement médical à l’ère de la médecine de précision

Le consentement libre et éclairé comme manifestation de l’adhésion à un acte thérapeutique en médecine est central dans la relation patient-médecin. Malgré d’importantes avancées, la médecine de précision fragilise la relation patient-médecin et ainsi la capacité du patient à consentir, du fait de la complexification de l’analyse des données disponibles et de l’intervention de nombreux médecins spécialistes dans la trajectoire des soins. Cet article propose d’interroger les conséquences de la médecine de précision sur la transmission et la nature de l’information, pour repenser la relation patient-médecin et les conditions de possibilité du consentement. Au-delà des impacts de la médecine de précision, nous pensons que le rôle du médecin s’apparente à celui d’un référent capable d’assurer la transmission et la cohérence des informations communiquées aux patients selon ses besoins en vue de restaurer sa compréhension de la maladie et des propositions thérapeutiques qui lui sont faites

La transplantation hépatique chez les patients co-infectés VIH/VHC et VIH/VHB

L’infection par le virus de l’immunodéficience humaine (VIH) a longtemps été considérée comme une contre-indication à la transplantation hépatique. Les raisons en étaient le pronostic sombre lié à la maladie VIH. L’avènement des trithérapies antirétrovirales a révolutionné le traitement des patients infectés par le VIH. Trente pour cent et 10 % des patients infectés par le VIH sont également infectés respectivement par le virus de l’hépatite C (VHC) et par le virus de l’hépatite B (VHB). L’hépatite chronique C et B semble progresser plus vite chez les patients co-infectés et un nombre important de patients développent une cirrhose menaçant le pronostic vital. La transplantation hépatique pose plusieurs problèmes dans ce contexte : (1) le risque d’accident d’exposition au sang lors de cette intervention longue et hémorragique ; (2) le moment de l’indication de la transplantation ; (3) l’interférence entre les antirétroviraux et les inhibiteurs de la calcineurine ; (4) le risque de récidive du VHB ou du VHC. Depuis 1999, un programme de transplantation hépatique chez les patients co-infectés a démarré avec le soutien de l’Agence nationale de recherche contre le sida et les hépatites. Les premiers résultats montrent une survie à 2 ans de 70 % des patients infectés par le VHC et de 100 % des patients infectés par le VHB. Il n’a pas été noté de progression accélérée de la maladie VIH. La récidive virale B est bien prévenue par l’association post-transplantation d’immunoglobulines spécifiques anti-HBs et d’analogues nucléosidiques et nucléotidiques efficaces contre le VHB. La difficulté majeure est la récidive virale C. L’identification de ses mécanismes, sa prévention et son traitement sont les futurs défis à résoudre

[Wilson's disease]

http://www.huveaux.fr/fr_santesite.aspWilson's disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene chromosome 13. The discovery of the gene allowed a better understanding of cytosolic copper trafficking its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This disease can be efficiently treated by chelation and zinc therapy. Liver transplantation is the therapy to patients with hepatic fulminant course, or in those with relentless progression of hepatic dysfunction in spite of medical therapy

Heterogeneous nuclear ribonucleoprotein A2/B1 identified as an autoantigen in autoimmune hepatitis by proteome analysis

International audienc