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We believe that it is essential to determine the presence of alcoholic steatohepatitis (ASH) on a histological basis not only for cases of diagnostic uncertainty but in all patients with severe (clinical) alcoholic hepatitis (AH) before starting corticosteroid treatment. In the absence of histological confirmation of ASH (10%–20% of cases), such treatment should not be initiated.

Acute alcoholic microvesicular steatosis (MIC) may complicate heavy alcohol intake and present as alcoholic hepatitis (AH) syndrome. However, detailed clinical, biological, and histologic data associated with MIC are scarce. We compared the clinical presentation, histologic features, and hepatic transcriptomic of patients presenting with AH due to either MIC or severe alcoholic steatohepatitis (ASH). In this case-control study, patients who drank heavily (>100 g/day) with the AH syndrome were included either in the MIC group (>50% severe microvesicular steatosis, no inflammation) or in the severe ASH group (polynuclear neutrophil infiltration, macrosteatosis, ballooned hepatocytes). All patients received standard supportive care plus steroids for those with severe ASH and were followed up for 3 months. Whole-liver transcriptome profiling was performed on liver snap-frozen biopsies. Compared to ASH (n = 24, mean age 49.3 years), patients in the MIC group (n = 12, mean age 49.1 years) had a higher reported alcohol intake (P < 0.01), lower Model for End-Stage Liver Disease score (P < 0.05), lower hepatic venous pressure gradient (P < 0.01), higher alanine aminotransferase (P < 0.02) and gamma-glutamyltransferase (P < 0.001), higher triglycerides (P < 0.001) and total cholesterol (P < 0.002), but similar bilirubin levels (P = 0.54). At histology, patients with MIC had a lower fibrotic stage compared to those with ASH (P < 0.001). A higher density of megamitochondria was seen in MIC compared to ASH (P < 0.05). During follow-up, death or transplantation occurred in 4/12 (33%) patients with MIC and 7/24 (29%) patients with severe ASH. Differential hepatic gene expression in MIC compared to ASH included down-regulation of genes related to inflammation and fibrosis and up-regulation of genes involved in lipid metabolism and mitochondrial function. Conclusion: MIC is an acute, noninflammatory, potentially severe alcoholic liver injury mimicking ASH, is associated with a lower

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Background and aims Liver stem cell therapy (SCT) is suggested as potential means to improve liver regeneration in advanced liver disease. However, data of randomized controlled trials are heterogeneous with no systematic histological evaluation. The aims of this study were firstly to specifically analyze the effect of autologous SCT on hepatic macrophages (implicated in liver regeneration) and second to perform an in depth transcriptome analysis in paired liver biopsies before and after transarterial administration of autologous hematopoietic stem cell in patients with alcoholic hepatitis. Methods Immunohistochemistry, in situ hybridization and global gene expression analysis were performed on liver biopsies of 58 patients (30 controls and 28 stem cell treated) both at baseline and after 4 weeks of follow-up. Results As reported in our initial report (Spahr et al., PlosOne 2013), patients who received SCT had a similar improvement of liver function over time as compared to controls and did not exhibit any increased proliferative activity in K7 positive liver progenitor cells nor in hepatocytes on the liver biopsy performed at 4 weeks. However, on repeat biopsy, patients who received SCT showed a more important CD68+ liver macrophagic expansion as compared to standard treatment (p<0.05). Transcriptome data revealed significant upregulated genes linked with inflammation (CD68, SAA, CXCL6), regeneration (SPINK1, HGF), fibrosis (COL1A) and stem cells (CD45). No major changes in gene pathways involved in liver growth, and in particular in cell cycle proteins were evidenced. SPINK1 mRNA identified as a good baseline prognostic factor (Lanthier et al., J Hepatol 2015) was present by in situ hybridization at week 4 in SCT patients in liver parenchyma areas adjacent to macrophage recruitment and liver cell proliferation. Conclusion The analysis of liver tissue after SCT demonstrated an expansion of macrophages concurrent with an upregulation in the expression of genes invol

Background and aims Liver stem cell therapy (SCT) is suggested as potential means to improve liver regeneration in advanced liver disease. However, data of trials and reports are heterogeneous with no systematic histological evaluation. In a recent randomized controlled trial (Spahr et al., PlosOne 2013), we observed that patients who received SCT had a similar improvement of liver function over time as compared to controls. The aims of this study were firstly to specifically analyze the effect of autologous SCT on liver cell proliferation and hepatic macrophages (implicated in liver regeneration) and second to perform an in depth transcriptome analysis in paired liver biopsies before and after transarterial administration of autologous hematopoietic stem cells in patients with alcoholic hepatitis. Methods Immunohistochemistry (Ki67, CK7 and CD68), in situ hybridization (SPINK1) and global gene expression analysis were performed on liver biopsies of 58 patients (30 controls and 28 stem cell treated) both at baseline and after 4 weeks of follow-up. Results Patients who received SCT did not exhibit any increased proliferative activity in hepatocytes nor in K7 positive liver progenitor cells on the liver biopsy performed at 4 weeks compared to controls. However, on repeat biopsy, patients who received SCT showed a more important CD68+ liver macrophagic expansion as compared to controls (p<0.05). Transcriptome data revealed significant upregulated genes linked with inflammation (CD68, SAA, CXCL6), regeneration (SPINK1, HGF), fibrosis (COL1A) and stem cells (CD45) in SCT patients compared to controls. No major changes in gene pathways involved in liver growth, and in particular in cell cycle proteins were evidenced between the two groups. SPINK1 mRNA identified as a good baseline prognostic factor (Lanthier et al., J Hepatol 2015) was present by in situ hybridization at week 4 in SCT patients in liver parenchyma areas adjacent to macrophage recruitment and liver cell pro

Cet article discute des nouveaux facteurs de bon pronostic identifiés dans l’hépatite alcoolique. Outre la prolifération des hépatocytes - phénomène évident mais pouvant être compromis en cas d’atteinte sévère du foie -, la prolifération des cellules progénitrices est désormais associée à un meilleur pronostic. Le rôle des macrophages hépatiques et de facteurs de croissance comme l'HGF, ou de prolifération comme le SPINK1 ou le TWEAK, est également discuté.

Introduction: Decompensated alcoholic liver disease (ALD) causes high morbidity and mortality. Factors associated with a poor clinical evolution, as well as the impact of liver atrophy linked with cirrhosis are poorly determined. The goal of this study is to explore the link between the liver volumetry calculated by computed tomography (CT) and the evolution of liver insufficiency in patients admitted for decompensated ALD. Materials and methods: Non-abstinent patients with acute decompensation of ALD (increase in serum bilirubin and deterioration of liver function) from a prospective study were included. This trial did not evidence any benefice of cellular therapy during the 3 months of follow up (Spahr L et al. Autologous bone marrow stem cell transplantation versus standard of care in patients with decompensated alcoholic liver disease: interim analysis of a RCT. Hepatology 2011;54:A62). Liver volumes evaluated by CT performed rapidly after patient admission were compared to further evolution of hepatic insufficiency, irrespective of treatment allocation. We defined patients with a ≥ 3 points decrease in MELD compared to baseline value as “improvers”, and those with less than 3 points decrease in MELD as “non-improvers”. Results: Fifty-eight patients were included. At admission, mean MELD score was 20.6 points. All patients had cirrhosis. Biopsy proven alcoholic steatohepatitis was diagnosed in 81% of cases. Patients with severe steatohepatitis (Maddrey score ≥ 32) were treated by steroids (66 %). 34 patients (59%) with a good evolution at 3 months (decrease in MELD score of 3 points or more) were classified as improvers meanwhile 24 patients (41%) were classified as non-improvers. Patients’ characteristics at admission depending on the 3 month evolution are reported in this table. Parameter Improvers n=34 Non-improvers n=24 P Age (years) 54 [35-63] 55 [44-67] 0.11 Hepatovenous pressure gradient (mmHg) 19.2 ± 2.7 19.2 ± 4.1 0.25 MELD score 20.7 ± 5.9 20.6 ± 3.3 0

Background and aims: The prognostic significance of liver progenitor cell (LPC) and macrophage expansion in the regeneration of decompensated alcoholic liver disease (ALD) remain ill defined. In a well-characterized population of patients with acutely decompensated ALD (Hepatology 2011, A62), we analysed macrophage infiltration, proliferative LPC and differential expression of hepatic genes at baseline in relation to outcome at 3 months follow up. Methods: Fifty-eight patients (MELD 20) were included. Liver biopsy at inclusion was used for (1) immunohistological analysis of proliferative LPC (MIB1+/CK7+), proliferative hepatocytes (MIB1+/CK7- parenchymal cells), morphometric analysis of macrophage infiltration (CD68) and LPC expansion (CK7), and (2) transcriptome profiling using Affymetrix GeneChip Human arrays. Serum levels of HGF were determined by immunoassay. A ≥ 3 points decrease in MELD at 3 months as compared to baseline defined the improvers. Fifteen abstinent cirrhotics served as controls. CD68 and SPINK3 mRNA expression was determined in various mice models of liver injury. Results: At baseline, patients with decompensated ALD presented a significant expansion of CD68+ macrophages and CK7+ cells compared to abstinent cirrhotics. Patients who will improve (n=34) were characterized at baseline by a higher number of CK7+/MIB1+ cells (1.9 ± 1.5 versus 0.9 ± 0.9 cells/field, p<0.01), MIB1+ hepatocytes (4.1 ± 3.6 versus 1.8 ± 1.4 cells/field, p<0.01), an increased expansion of liver macrophages (4.4% versus 3.3% of surface area, p<0.05) and a higher level of serum HGF (p<0.05), compared to those who will not (n=24). Transcriptome analysis revealed that the first pathways upregulated in improvers were related to cell cycle and a 7-fold increase of liver serine peptidase inhibitor Kazal type I (SPINK1) compared with non-improvers (p=0.005). SPINK1 liver expression positively correlated with CD68 (r=0.46) and cyclinE1 (r=0.6). In mice, a 20-fold increase in liver S

Clinical challenge and images in gastro-enterology.

Alcoholic liver disease is a spectrum of lesions, of which the most severe is alcoholic steatohepatitis (ASH). Recent European guidelines define alcoholic hepatitis as a clinical syndrome: the recent onset of jaundice and/or ascites in a patient with ongoing alcohol misuse. Next to infection, the most frequent aetiology is ASH, a histological diagnosis. In case of severe ASH, as defined by prognostic scores, a biopsy is needed to confirm the diagnosis. Non-severe forms of ASH may improve with interruption of alcohol abuse only; however survival of severe forms of ASH is improved by the association of corticosteroids and N-acetylcysteine. In case of uncontrolled infection, pentoxifylline may be administered. The Lille score, measured at the 7th day of corticosteroid therapy, measures response to therapy and guides the total duration of treatment.

Background The relationship between portal pressure and architectural distortion in general, and fibrosis in particular, remains ill defined in patients with chronic liver diseases. We performed a morphometric analysis of fibrosis using a computer assisted method on liver biopsy specimens obtained during transjugular liver biopsy in 19 consecutive patients admitted for decompensated alcoholic liver disease. The hepatic venous pressure gradient (HVPG) was obtained in all patients. Liver biopsy was performed using a TJL 9F aspiration type needle (Cook), with a mean 2.5 passes. Mean fibrosis area (MFA) was expressed as the percentage of the total area of liver tissue specimen. Results Patients characteristics are given in Table (median, range). Liver biopsy provided fragmented samples but were appropriate for a complete histological evaluation in all cases. Cirrhosis was diagnosed in all patients, but the number and thickness of fibrous septa were variable among cases. n 19 Age (yrs) 55 [35-69] Histological criteria for alcoholic steatohepatitis 10/19 HVPG (mmHg) 17 [4-23] MFA (%) 11.5 [2-42] Cirrhosis (%) 100 MELD score 18.5 MFA showed a weak correlation with portal pressure, as assessed by HVPG (r=0.29), and with the wedge hepatic pressure (r=0.21). Conclusions In patients with decompensated alcoholic liver disease, fibrosis area measured by morphometry on liver biopsy specimens correlates poorly with portal pressure. We hypothesized that fragmentation of liver tissue in relation with the transvenous aspiration technique, the sampling variability, as well as the dynamic vascular component of portal hypertension overexpressed in alcoholic steatohepatitis may explain in part these results.

We aimed to study the hepatic differentially expressed genes associated with 1) bone marrow stem cell therapy (BMST) and 2) the evolution of liver function during follow-up in a well-characterized patients’ population of acutely decompensated alcoholic liver disease (ALD). Methods: This study derives from the material and bio-clinical data issued from a trial of autologous bone marrow stem cell transplantation in patients with ALD (Hepatology 2011, A62), for which an informed consent was obtained in all cases. Transcriptome profiling was performed on snap liver frozen samples with Affymetrix GeneChip Human arrays containing 43134 transcripts. Differential gene expression was analyzed on liver tissue obtained at the 4-week follow-up visit after BMST (n=12) or after standard medical therapy alone (n=12). We also compared differentially expressed transcripts on baseline biopsy performed early after admission, according to the evolution of liver insufficiency at 3 months, irrespective of treatment allocation. We defined patients with a ≥ 3 points decrease in MELD compared to baseline value as “improvers” (n=17), and those with less than 3 points decrease in MELD as “non improvers” (n=13). Serum soluble receptor of TNF (STNF) and hepatocyte growth factor (HGF) were measured. Results: 1) Autologous BMST did not provide any clinical, biological or histological benefits compared to standard medical therapy (Hepatology 2011, A62). However, in stem cell treated patients, at a 5% false discovery rate, gene expression changes at 4 weeks of follow-up were predominantly associated with inflammation and immune chemotaxis (SAA, CXCL6, CXCL13, CCL19), as well as in hematopoietic cell protein (CD45), compared to patients with standard therapy alone. 2) Differentially expressed genes in baseline biopsy characterized the “improvers” and the “non-improvers”. Genes involved in cell cycle mitosis (cyclin A and B, CDK1, CDC20) were upregulated in improvers compared to non-improvers, as wel

Background: Liver regeneration plays a key role in the prognosis of acute-on-chronic ALD. Both hepatic progenitor cell (HPC) and liver macrophages increase in response to acute liver injury, but the prognostic significance of these changes remains to be determined. We studied the expansion of both macrophage and proliferative HPC compartments on liver biopsies obtained from the bone marrow stem cell trial in ALD, and correlated with the outcome at 3 months. Methods: 58 patients with decompensated ALD (MELD 19) were included. Proliferative HPC were analyzed (immunohistochemistry) on liver biopsy performed at admission, by manual count of Ki67+/CK7+ and CK7-cells. Macrophage expansion was determined by CD68+ morphometric analysis. Cytokines and markers of regeneration were measured by immunoassays on serum and quantitative PCR on liver tissue. A ≥ 3 points decrease in MELD at 3 months defined the responders. Results Responders Non responders CK7+/Ki67+ cells (HPC) 1.9±1.5 0.9±0.9 0.01 CK7-/Ki67+ cells (mature hepatocytes) 4.1±3.6 1.8±1.4 0.01 Liver macrophages (% of surface area) 4.4% 3.3% 0.05 Both hepatocyte growth factor and soluble TNF receptor serum levels were higher in responders. Liver PCR analysis showed that liver macrophagic expansion was associated with an increase in TWEAK receptor mRNA expression (p<0.05), known to stimulate HPC proliferation. Conclusion: This is the first study showing that markers of liver cell proliferation obtained on baseline liver biopsy predicts the clinical outcome at 3 months in patients with decompensated ALD. These data support the role of liver biopsy not only for diagnostic purposes but also to determine the short term prognosis.

Background In decompensated ALD, autologous transplantation of bone marrow mononuclear cells doesn’t improve liver function at 3 months as compared to standard of care (Hepatology 2011, Abstract). We aim to analyze changes in hepatic progenitor cell (HPC) and macrophage compartments associated with this strategy. Methods: We examined liver biopsies obtained at baseline and at 4 weeks of follow-up in 58 patients. Both HPC and macrophage compartments were analyzed using immunohistochemistry for CK7 and CD68 and morphometric analysis. Results Immunohistochemical staining for CK7 correlated with liver failure as assessed by the MELD score both at baseline (r=0.33; p<0.05) and at 4-week biopsies (r=0,61; p<0,01), in line with recently published data (Sancho-Bru, Hepatology 2012). Autologous transplantation procedure was not associated with changes in CK7 positive cells at 4-week follow-up biopsy. Table: (CD68 expressed in % of surface area) Treatment Group Baseline CD68 (%) 4-week CD68 (%) P value Bone marrow 3.7 5.4 0.01 Standard of care 4.2 4.6 NS Further analyses of gene expression patterns are planned in order to determine whether those changes in the macrophage compartment are associated modifications in inflammatory or regenerative pathways. Conclusion Total liver cell CK7 positivity correlates with the degree of liver failure in patients with ALD. Autologous mononuclear bone marrow cell infusion doesn’t increase the number of HPC as compared to standard of care alone, but is associated with an expansion of the macrophage compartment. This is of particular interest, knowing the role of the micro-environment in HPC polarization.

The Gcm/Glide transcription factor is transiently expressed and required in the Drosophila nervous system. Threshold Gcm/Glide levels control the glial versus neuronal fate choice, and its perdurance triggers excessive gliogenesis, showing that its tight and dynamic regulation ensures the proper balance between neurons and glia. Here, we present a genetic screen for potential gcm/glide interactors and identify genes encoding chromatin factors of the Trithorax and of the Polycomb groups. These proteins maintain the heritable epigenetic state, among others, of HOX genes throughout development, but their regulatory role on transiently expressed genes remains elusive. Here we show that Polycomb negatively affects Gcm/Glide autoregulation, a positive feedback loop that allows timely accumulation of Gcm/Glide threshold levels. Such temporal fine-tuning of gene expression tightly controls gliogenesis. This work performed at the levels of individual cells reveals an undescribed mode of Polycomb action in the modulation of transiently expressed fate determinants and hence in the acquisition of specific cell identity in the nervous system. © 2012 Popkova et al.

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Variante(s) de titre : Histoire et patrimoine hospitalier, Variante(s) de titre : Histoire & patrimoine hospitalier et mémoire de la médecine à Strasbourg, Variante(s) de titre : Histoire & patrimoine hospitalier : revue de l'Association Les Amis des hôpitaux universitaires de Strasbourg, Variante(s) de titre : Histoire & patrimoine hospitalier : mémoire de la médecine à Strasbourg : revue de l'Association Les Amis des hôpitaux universitaires de Strasbourg et du Département d'Histoire de la médecine, Périodicité : Irrégullier, Appartient à l’ensemble documentaire : BNUStrSoc, Appartient à l’ensemble documentaire : Alsace1, Appartient à l’ensemble documentaire : BNUStr000