A Pitfall in the Diagnosis of Unresectable Liver Metastases: Multiple Bile Duct Hamartomas (von Meyenburg Complexes)

Von Meyenburg complexes (VMC) are a cluster of benign liver malformations including biliary cystic lesions, with congenital fibrocollagenous stroma. This rare entity can mimick multiple secondary hepatic lesions. We report a case of a 56-year-old woman who had multiples liver lesions 12 years after operation for breast cancer. Biopsy of the hepatic lesion confirmed the diagnosis of VMC. Preoperative discovery of multiple gray-white nodular lesions scattered on the surface of the liver should not always contraindicate curative liver resection. The diagnosis of VMC should be known and confirmed with liver biopsy

Clinical Study A Reappraisal of Chemotherapy-Induced Liver Injury in Colorectal Liver Metastases before the Era of Antiangiogenics

Background and Aims. Chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. We describe these lesions and assess risk factors and impacts on postresection morbidity and mortality in naive patients to chemotherapy before the era of bevacizumab. Methods. Noncancerous liver tissue lesions were analysed according to tumour, chemotherapy, surgery, and patient characteristics. Results. Fifty patients aged 62 ± 9.3 years were included between 2003 and 2007. Thirty-three (66%) received chemotherapy, with Folfox (58%), Folfiri (21%), LV5FU2 (12%), or Xelox (9%) regimens. Hepatotoxicity consisted of 18 (36%) cases of severe sinusoidal dilatation (SD), 13 (26%) portal fibrosis, 7 (14%) perisinusoidal fibrosis (PSF), 6 (12%) nodular regenerative hyperplasia (NRH), 2 (4%) steatosis >30%, zero steatohepatitis, and 16 (32%) surgical hepatitis. PSF was more frequent after chemotherapy (21% versus 0%, = 0.04), especially LV5FU2 ( = 0.02). SD was associated with oxaliplatin (54.5% versus 23.5%, = 0.05) and low body mass index ( = 0.003). NRH was associated with oxaliplatin ( = 0.03) and extensive resection ( = 0.04). No impact on mortality and morbidity was observed, apart postoperative elevation of bilirubin levels in case of PSF ( = 0.03), longer hospitalization in case of surgical hepatitis ( = 0.03), and greater blood loss in case of portal fibrosis ( = 0.03). Conclusions. Chemotherapy of colorectal liver metastases induces sinusoidal dilatation related to oxaliplatin and perisinusoidal fibrosis related to 5FU, without any impact on postoperative mortality

The treatment response of chronically hepatitis C virus-infected patients depends on interferon concentration but not on interferon gene expression in peripheral blood mononuclear cells.

International audienceThe current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome

Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis: Hepatology

We identified in the transcriptome analysis of patients with alcoholic hepatitis (AH) osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, Western blotting and ELISA. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH compared to normal livers and other types of chronic liver diseases and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and MMP-7) and cleaved-OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C SNP of the OPN gene compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by LPS and stimulated inflammatory actions in hepatic stellate cells

Refinement of 1p36 Alterations Not Involving PRDM16 in Myeloid and Lymphoid Malignancies

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

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

Etude des corrélations entre les paramètres biochimiques sanguins et ascitiques chez des malades atteints de cirrhose

[Résumé français]Le traitement médical de l'ascite du patient cirrhotique nécessite une surveillance du ionogramme sanguin et de la fonction rénale. Ces paramètres pourraient être prélevés directement sur le liquide d'ascite, afin de simplifier les modalités pratiques de surveillance du traitement diurétique.L'étude était prospective et multicentrique sur 70 patients cirrhotiques avec une cirrhose. La corrélation était très forte entre les concentrations dans le sang et l'ascite pour le Na, K, CI, Urée, créatinine, ce qui pourrait permettre de se passer de la veinoponction dans certains cas.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Évaluation de l'élastométrie impulsionnelle ultrasonore (Fibroscan®) dans le dépistage de la fibrose hépatique chez les patients consommateurs chroniques et excessifs d'alcool

Le diagnostic précoce de la fibrose hépatique asymptomatique d'origine alcoolique est difficile. L'élastométrie impulsionnelle ultrasonore est une méthode non invasive pouvant remplacer avantageusement la biopsie hépatique. But : Évaluer la performance diagnostique du Fibroscan® dans le domaine des maladies alcooliques du foie, en comparaison au Fibrotest® et au dosage de l'acide hyaluronique. Patients et méthodes : Les patients consommant au moins 50g/j d'alcool pendant plus de 5 ans bénéficiaient d'une biopsie hépatique, d'un Fibroscan®, d'un Fibrotest® et du dosage sérique de l'acide hyaluronique. La fibrose hépatique était évaluée selon le score METAVIR. La corrélation entre fibrose et élasticité hépatique était étudiée et les seuils diagnostiques déterminés par les courbes ROC. Résultats : D'avril 2005 à mai 2006, 61 patients d'âge moyen 50,5+-9,7 ans ont été inclus. Les valeurs d'élasticité étaient entre 2,8 et 75kPa. Seule la fibrose METAVIR était significativement corrélée à l'élasticité hépatique (r=0,72, p=1), 0,89 (F>=2), 0,90 (F>=3) et 0,94 (F=4), permettant de retenir les seuils diagnostiques d'élasticité à 6 (F>=1), 7,9 (F>=2), 11,3 (F>=3) et 19 kPa(F4) avec une sensibilité et une spécificité proches de 85%. Le Fibroscan® avait une meilleure performance diagnostique que le Fibrotest® et l'acide hyaluronique avec des aires sous la courbe ROC plus élevées pour tous les stades de fibrose (0,77 (F>=1), 0,82 (F>=2), 0,76 (F>=3), 0,77 (F=4) pour le Fibrotest®, et 0,70 (F>=1), 0,81 (F>=2), 0,86 (F>=3), 0,77 (F=4) pour l'acide hyaluronique). Conclusion : Le Fibroscan® est performant pour le diagnostic de la fibrose alcoolique asymptomatique, s'avérant supérieur au Fibrotest® et à l'acide hyaluronique. Ces résultats ouvrent de nouvelles perspectives dans la prise en charge de patients consommateurs excessifs et chroniques d'alcool.AMIENS-BU Santé (800212102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Valeurs diagnostiques et pronostiques de la cytokératine 18 dans l'hépatite alcoolique aiguë sévère

Introduction : L hepatite alcoolique aigue (HAA) s accompagne de phenomenes d apoptose et de necrose. L anticorps M30 detecte un neoepitope de la cytokeratine 18 (CK18) apparaissant lors de l apoptose, M65 detectant la CK 18 entiere. Patients et méthodes : Les fragments de la CK18 ont ete doses chez 159 patients (76 HAA severes, 38 cirrhoses sans HAA, 45 temoins sains) avec les kits M30 ApoptosenseR ELISA et M65R ELISA (Peviva AB). L objectif principal a ete de rechercher les variables permettant le diagnostic d HAA. Résultats : Les moyennes de M30, M65 et de M30/M65 etaient differentes entre les 3 groupes (ANOVA, tous les p<0,0001). Parmi ces marqueurs, M30 avait la meilleure valeur diagnostique (AUROC=0,825). En analyse multivariee, la difference entre les groupes HAA et cirrhose etait significative pour M30 (OR=1,004), l uree (OR=0,64), le score de Child-Pugh (OR=2,72) et le score de Maddrey (OR=1,20). Un nouveau score developpe a partir des variables discriminantes (DF M30 = -19,04 + 0,179 x Score de Maddrey - 0,448 x Uree + 0,004426869 x M30 + 1,002 x Score de Child-Pugh) avait une AUROC a 0,985, superieure a celle du score de Maddrey (p=0,04) et du MELD (p=0,003). La valeur seuil de 0,617 pour le diagnostic d HAA severe avait une sensibilite de 96,7 % et une specificite de 94,4 %. Enfin, M30 et M65 n etaient pas correles a la survie a 6 mois. Conclusion : Le DF M30 presente de bonnes caracteristiques diagnostiques, et pourrait permettre de surseoir a la biopsie hepatique necessaire dans les formes severes d HAA mais doit etre confirmee dans une cohorte de validation.Background : Acute alcoholic hepatitis (AAH) is associated with both apoptosis and necrosis phenomena. M30 antibody detects a specific caspase-cleaved neoepitope of cytokeratin 18 (CK18) whereas M65 detects all forms of CK 18s. Patients and methods : CK18 fragments were assessed in 159 patients (76 severe AAH, 38 cirrhosis without AAH and 45 controls) with M30 ApoptosenseR ELISA and M65R ELISA kits (Peviva AB). Primary objective was to identify variables associated with the diagnosis of severe AAH. Results : Mean M30, M65 and M30/M65 ratio were significantly different between the three groups (ANOVA, all p<0,0001). Among these markers, M30 had the best diagnostic value (AUROC=0,825). Multivariate analysis between severe AAH and cirrhosis group was significant for M30 (OR=1,004), uremia (OR=0,64), Child-Pugh score (OR=2,72) and discriminant function (OR=1,20). A new score including the discriminant variables (DF M30 = -19,04 + 0,179 x Discriminant function - 0,448 x Uremia + 0,004426869 x M30 + 1,002 x Child-Pugh score) had an AUROC of 0,985 and was significantly higher than Discriminant function (p=0,04) and MELD score (p=0,003). The best cut-off for the diagnosis of severe AAH was 0,617 with a sensitivity of 96,7 % and a specificity of 94,4 %. Finally, M30 and M65 were not correlated with the 6 month survival. Conclusion : The DF M30 is accurate for the diagnosis of severe AAH, and could therefore allow to avoid liver biopsy that is needed before treatment, but has to be confirmed in a validation cohort.AMIENS-BU Santé (800212102) / SudocSudocFranceF