Nathalie Sturm

University of Grenoble, Grenoble, Rhône-Alpes, France

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Publications (109)571.34 Total impact

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    ABSTRACT: Background & aims: The pro-inflammatory cytokine IL-17 plays a crucial role in liver diseases associated with hepatic fibrosis and increased risk of cancer development. Nevertheless, the cellular source of this cytokine has never been characterised in patients with liver fibrosis. Methods: In this study, we investigated liver biopsies from 49 patients with chronic viral hepatitis at different stages of liver fibrosis. We monitored IL-17 production by intracellular flow cytometry, immunofluorescence and immunohistochemical in situ stainings, allowing a precise quantification, characterization, and localization of IL-17(+) cells. Results: Density of IL-17(+) cells increased with the stage of liver fibrosis specifically in fibrotic septa and portal areas (correlation coefficient r = 0.7373; p<0.0001). Data clearly show that the frequency of intrahepatic IL-17(+) lymphocytes (including T, NKT and NK cells) was independent on stage of liver fibrosis and we observed no statistical differences in number of IL-17(+) macrophages during progression of fibrosis. On the other hand, the number of IL-17(+) neutrophils in fibrotic septa and portal areas strongly correlated with the stages of fibrosis (correlation coefficient r = 0.6986; p<0.0001), contributing significantly to total IL-17 production in liver tissue. Conclusions: Our data indicate that neutrophils represent an important source of IL-17 in the human liver, especially in late fibrosis stages. Inhibition of this specific harmful subset of neutrophils may offer therapeutic opportunities in fibrotic liver. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Liver international: official journal of the International Association for the Study of the Liver
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    ABSTRACT: Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma. Immune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8β, FoxP3, IL-6, IFN-γ, perforin, RANTES) were analyzed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues. Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, high density of CD8(+) cells in cirrhotic areas away from the tumor was an independent prognostic factor for tumor recurrence after resection, further validated in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells ≥100/field was associated with significant higher tumor recurrence (p=0.003) and lower overall survival (p=0.05) at 5 years. High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumor recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · Liver international: official journal of the International Association for the Study of the Liver
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    ABSTRACT: The goal of this study was to evaluate the diagnostic accuracy of a software program that automatically analyzes the liver surface to diagnose significant fibrosis, by comparing it to the subjective analysis of a radiologist and to transient elastography (Fibroscan(®)). One hundred fourteen patients with chronic liver disease were included in the study. They underwent liver biopsy, FibroScan(®) and ultrasonographic examination of the liver surface. The liver surface was analyzed by a software program that gave a score of surface irregularities. This evaluation was compared to subjective analysis by a radiologist expert in liver imaging and by two general radiologists. Fifty percent of the patients had significant fibrosis according to the METAVIR score. The AUROC for the diagnosis of significant fibrosis by the software program was 0.80 (95%CI: 0.71-0.87), which was equivalent (P=0.86) to that of FibroScan(®) (0.81; 95%CI: 0.71-0.89). Results of the subjective analysis by the expert radiologist were poorer than those of the software analysis (P=0.02) (AUROC=0.66; 95%CI: 0.56-0.75). Interobserver agreement among radiologists was poor (0.25<kappa<0.37). Computer-assisted liver surface analysis was better than subjective analysis, and similar to that of the FibroScan(®). This method could be useful for the diagnosis of significant fibrosis in patients with chronic hepatitis and complementary to the other non-invasive diagnostic tests. Copyright © 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
    No preview · Article · Apr 2015 · Diagnostic and interventional imaging

  • No preview · Article · Apr 2015 · Journal of Hepatology

  • No preview · Article · Oct 2014
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    ABSTRACT: Background & aims Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of Fibrotest®, Fibrometer® and Hepascore® for liver fibrosis in hepatitis B compared to hepatitis C. Methods 510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR. Results Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F ⩾3 were underestimated: Fibrotest®: 47% versus 26%, Fibrometer®: 24% versus 6%, Hepascore®: 41% versus 24%, p<0.01. Multivariate analysis showed that hepatitis B (0R 3.4, CI95% 1.2-19.2, p<0.02) and low γGT (OR 7.3, CI95% 2.0-27.0, p<0.003) were associated with fibrosis underestimation. Conclusion Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut-offs.
    No preview · Article · Jul 2014 · Journal of Hepatology
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    ABSTRACT: During chronic hepatitis C virus (HCV) infection, the role of intra-hepatic (IH) natural killer (NK) cells is still controversial. To clarify their functions, we investigated anti-viral and cytotoxic activity of NK cells in human fresh liver biopsies. We compared the functions of IH-NK cells in HCV-infected and NASH patients in physiological conditions as well as after stimulation using flow cytometric and immunohistochemical analyses. Interestingly, few IH-NK cells produced anti-viral cytokine IFN-γ in HCV-infected patients similarly as in non-infected individuals. Spontaneous degranulation activity was extremely low in peripheral NK cells compared to IH-NK cells, and was significantly higher in IH-NK cells from HCV-infected patients compared to non-infected individuals. Immunohistochemical analysis revealed that perforin granules were polarized at the apical pole of IH-NK cells. The presence of CD107a and perforin in IH-NK cells demonstrated that NK cells exerted a cytolytic activity at the site of infection. Importantly, IH-NK cell functions from HCV-infected patients were inducible by specific exogenous stimulations. Upon ex vivo K562 target cell stimulations, the number of degranulating NK cells was significantly increased in the pool of IH-NK cells compared to circulating NK cells. Interestingly, after stimulation, the frequency of IFN-γ-producing IH-NK cells in HCV-infected patients was significantly higher at early stage of inflammation whereas the spontaneous IH-NK cell degranulation activity was significantly impaired in patients with highest inflammation and fibrosis Metavir scores. Our study highlights that some IH-NK cells in HCV-infected patients are able to produce INF-γ and degranulate and that those two activities depend on liver environment including the severity of liver injury. Thus, we conclude that critical roles of IH-NK cells have to be taken into account in the course of the liver pathogenesis associated to chronic HCV infection.
    Full-text · Article · Apr 2014 · PLoS ONE
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    ABSTRACT: Background Liver stiffness evaluation (LSE) by Fibroscan is now widely used to assess liver fibrosis in chronic hepatitis C. Liver steatosis is a common lesion in chronic hepatitis C as in other chronic liver diseases, but its influence on LSE remains unclear. We aimed to precisely determine the influence of steatosis on LSE by using quantitative and precise morphometric measurements of liver histology. Methods 650 patients with chronic hepatitis C, liver biopsy, and LSE were included. Liver specimens were evaluated by optical analysis (Metavir F and A, steatosis grading) and by computerized morphometry to determine the area (%, reflecting quantity) and fractal dimension (FD, reflecting architecture) of liver fibrosis and steatosis. Results The relationships between LSE and liver histology were better described using morphometry. LSE median was independently linked to fibrosis (area or FD), steatosis (area or FD), activity (serum AST), and IQR/LSE median. Steatosis area ≥4.0 % induced a 50 % increase in LSE result in patients with fibrosis area <9 %. In patients with IQR/LSE median ≤0.30, the rate of F0/1 patients misclassified as F ≥ 2 by Fibroscan was, respectively for steatosis area <4.0 and ≥4.0 %: 12.6 vs 32.4 % (p = 0.003). Steatosis level did not influence LSE median when fibrosis area was ≥9 %, and consequently did not increase the rate of F ≤ 3 patients misclassified as cirrhotic. Conclusion A precise evaluation of liver histology by computerized morphometry shows that liver stiffness measured by Fibroscan is linked to liver fibrosis, activity, and also steatosis. High level of steatosis induces misevaluation of liver fibrosis by Fibroscan.
    Full-text · Article · Mar 2014 · Journal of Gastroenterology
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    ABSTRACT: Background: The polymorphisms of IFNL4 are strongly associated with both spontaneous hepatitis C virus (HCV) clearance and response to peg-IFN-α/ribavirin treatment. To further establish the biological effects of the IFNL4 and rs1297860 variations, we studied the activity of liver immune cells. Methods: Fresh liver samples were collected from HCV-infected patients before any treatment and from NASH patients as controls. Degranulation activity of each lymphocyte type was assessed by the surface expression of CD107a. IFNL4 polymorphisms and HCV genotypes were determined. Results: In the liver, frequency of CD107a(+) immune cells was significantly higher in HCV patients compared to NASH patients. Higher degranulation activity was observed in lymphocytes of HCV patients with favorable IFNL4 genotypes compared to patients with unfavorable genotypes. Multivariate regression analyses indicated that serum ALT levels were dependent on both Metavir activity score and frequency of CD107a positive NKT cells. The high level of degranulation activity observed before treatment was associated with a high HCV RNA decline at the early stage of peg-IFN-α/ribavirin treatment in patients with favorable genotypes. Conclusions: These data underline that intrahepatic lymphocyte degranulation activity in HCV-infected patients is associated with IFNL4 polymorphisms and contributes to the clearance of HCV in patients with favorable genotypes under antiviral therapy.
    Full-text · Article · Jan 2014 · The Journal of Infectious Diseases
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    ABSTRACT: Morphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal-bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal-bridging and perisinusoidal fibrosis, whereas portal-bridging area was predominant in cirrhosis. Measurement of portal-bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal-bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal-bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal-bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal-bridging fibrosis area (first step, P<0.001), the steatosis area (second step, P<0.001), and the Metavir A grade (third step, P=0.001), but not to the perisinusoidal fibrosis area. Automated quantification in a large cohort of chronic hepatitis C showed that perisinusoidal fibrosis progressively grew in early fibrosis stages but did not increase in septal or cirrhotic stages and that the portal-bridging fibrosis area appeared as a more accurate tool to assess fibrosis progression than the whole fibrosis area.Modern Pathology advance online publication, 3 January 2014; doi:10.1038/modpathol.2013.225.
    No preview · Article · Jan 2014 · Modern Pathology
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    ABSTRACT: Inflammatory hepatocellular adenomas (IHCAs) are benign liver lesions that can be characterized histologically by the presence of an inflammatory infiltrate and at the molecular level by the overexpression of acute phase inflammatory response genes. Recurrent somatic mutations of the interleukin-6 (IL-6) signal transducer (IL6ST) locus, encoding the critical component of the IL-6 signal transduction machinery gp130, are present in 60% of IHCAs and in a subset (2%) of hepatocellular carcinoma (HCCs). By screening of 256 human hepatic adenoma specimens (the largest genetic analysis of IL6ST performed to date in this setting), we identified 24 distinct somatic IL6ST mutations among 66 mutant adenomas. The functional analysis of nine different gp130 mutants expressed in hepatic cancer cell lines consistently revealed the constitutive and IL-6-independent activation of the JAK/STAT signaling pathway. We further demonstrated that the signaling activity of mutant gp130 in IHCA remains responsive to suppressor of cytokine signaling 3 (SOCS3), a physiological gp130 inhibitor. Specifically, cells expressing a double mutant variant of gp130 with a disrupted SOCS3-binding site at residue 759 (Y186/Y759F) displayed a hyperactivation of signal transducer and activator of transcription 3 (STAT3) as compared with cells expressing the endogenous IHCA-associated Y186 gp130 mutant. Notably, we identified that constitutive signaling via gp130 in IHCA requires the Janus kinase family member JAK1, but not JAK2 or tyrosine kinase 2. In support of this notion, AG490, a tyrosine kinase inhibitor that selectively blocks JAK2, had no effect on gp130 activity. In stark contrast, we showed that ruxolitinib, a JAK1/JAK2-selective tyrosine kinase inhibitor used to treat patients with myelofibrosis, dramatically impaired JAK1-STAT signaling downstream of all IHCA-associated gp130 mutants. In conclusion, our findings provide a rationale for the use of JAK1 inhibitors for the treatment of HCAs expressing mutant gp130 as well as a subset of HCCs that bear similar mutations.
    Full-text · Article · Dec 2013 · OncoImmunology
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    ABSTRACT: Objective The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. Methods ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5’-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. Results AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r = 0.129, P < 0.0035). The ROC curve analyses showed that the AST/ALT ratio does not discriminate significant fibrosis (F ≥ 2) (AUROC = 0.531) and had only very poor diagnostic accuracies for severe fibrosis (F ≥ 3) (AUROC = 0.584) or cirrhosis (F4) (AUROC = 0.626). Conclusion AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations.
    No preview · Article · Nov 2013 · Gastroentérologie Clinique et Biologique
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    ABSTRACT: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed to investigate the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated by RFA. All consecutive naive patients from 3 university hospitals with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta-catenin, epithelial cell adhesion molecule (EpCAM) and endothelial cell-specific molecule 1(ESM-1) were assessed. Main clinical end-points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-Rang Test and Cox models. 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51 and 12 patients respectively. Median follow-up was 27 months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expressions of EpCAM and surrogate markers of activation of the Wnt-ßcatenin pathway. The 2 independent predictive factors for overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p = 0.045), and ESM-1 expression (HR 1.56 [1.004; 2.43], p = 0.048). ESM-1 expression was also an independent predictive factor for early recurrence (HR 1.81 [1.02; 3.21], p = 0.042). ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value for early recurrence after RFA.
    No preview · Article · Aug 2013 · Journal of Hepatology
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    ABSTRACT: We aimed to evaluate the expression and diagnostic value of five immunohistochemical markers (HBME-1, Galectin-3, CK19, CD56 and p63) in a very large series of unequivocal papillary thyroid carcinoma (PTC) cases, including both the classic (CPTC) and the follicular variant (FVPTC). We performed an immunohistochemical analysis on a tissue micro-array of 204 PTCs (98 CPTCs, 90 FVPTCs, and 16 other variants). HBME-1 was the most sensitive marker, staining 95.9% of CPTCs and 81.1% of FVPTCs. CD56, a marker whose expression is reduced or absent in thyroid carcinoma, revealed a negative, "malignant" profile in 93.9% of CPTCs and 73.3% of FVPTCs. Galectin-3, CK19 and p63 were positive in 64.7%, 45.6% and 6.9% of PTCs, respectively. The immunopanel consisting of HBME-1, CD56 and/or CK19 reached the highest sensitivity (95.6%). The co-expression of 2 or more proteins was observed in 88.2% of PTCs, with HBME-1 and CD56 being the most frequent positive association (79.4%). We report a new panel of antibodies consisting of HBME-1, CK19 and CD56 that was found to be highly sensitive for both CPTC and FVPTC. This panel could be recommended as a supplement to the morphological criteria in the diagnosis of difficult FVPTC cases.
    No preview · Article · Jul 2013 · Pathology - Research and Practice

  • No preview · Article · Apr 2013
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    Dataset: Text S1
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    ABSTRACT: Details of laboratory tests with formulae for the calculation of the scores. (DOC)
    Preview · Dataset · Mar 2013
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    Dataset: Text S2
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    ABSTRACT: Details of calculation of costs for the economic analysis. (DOC)
    Preview · Dataset · Mar 2013
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    Dataset: Figure S2
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    ABSTRACT: Principal Component Analysis of the five main tests. (TIF)
    Preview · Dataset · Mar 2013
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    Dataset: Text S3
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    ABSTRACT: The ANRS HCEP-23 FIBROSTAR study group. (DOC)
    Preview · Dataset · Mar 2013
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    ABSTRACT: We aimed to determine the best algorithms for the diagnosis of significant fibrosis in chronic hepatitis C (CHC) patients using all available parameters and tests. We used the database from our study of 507 patients with histologically proven CHC in which fibrosis was evaluated by liver biopsy (Metavir) and tests: Fibrometer®, Fibrotest®, Hepascore®, Apri, ELFG, MP3, Forn's, hyaluronic acid, tissue inhibitor of metalloproteinase-1 (TIMP1), MMP1, collagen IV and when possible Fibroscan™. For the first test we used 90% negative predictive value to exclude patients with F≤1, next an induction algorithm was applied giving the best tests with at least 80% positive predictive value for the diagnosis of F≥2. The algorithms were computed using the R Software C4.5 program to select the best tests and cut-offs. The algorithm was automatically induced without premises on the part of the investigators. We also examined the inter-observer variations after independent review of liver biopsies by two pathologists. A medico-economic analysis compared the screening strategies with liver biopsy. In "intention to diagnose" the best algorithms for F≥2 were Fibrometer ®, Fibrotest®, or Hepascore® in first intention with the ELFG score in second intention for indeterminate cases. The percentage of avoided biopsies varied between 50% (Fibrotest® or Fibrometer®+ELFG) and 51% (Hepascore®+ELFG). In "per-analysis" Fibroscan™+ELFG avoided liver biopsy in 55% of cases. The diagnostic performance of these screening strategies was statistically superior to the usual combinations (Fibrometer® or Fibrotest®+Fibroscan™) and was cost effective. We note that the consensual review of liver biopsies between the two pathologists was mainly in favor of F1 (64-69%). The ELFG test could replace Fibroscan in most currently used algorithms for the diagnosis of significant fibrosis including for those patients for whom Fibroscan™ is unusable.
    Full-text · Article · Mar 2013 · PLoS ONE

Publication Stats

2k Citations
571.34 Total Impact Points

Institutions

  • 2003-2015
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
  • 2009-2014
    • University Joseph Fourier - Grenoble 1
      • Institut Albert Bonniot
      Grenoble, Rhône-Alpes, France
  • 2001-2013
    • Centre Hospitalier Universitaire de Grenoble
      • Département d'Anatomie et Cytologie Pathologiques
      Grenoble, Rhône-Alpes, France
  • 2012
    • UNIT
      Miami, Florida, United States
  • 2007-2011
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2004-2006
    • Laboratoire d'Informatique de Grenoble
      Grenoble, Rhône-Alpes, France