Gabriel Perlemuter

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (85)336.46 Total impact

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    ABSTRACT: Homing of inflammatory cells to the liver is key in the progression of non-alcoholic steatohepatitis (NASH). An abnormal response of CD4+ T cells from obese mice to the chemotactic effect of CXCL12 has been reported but the mechanism involved in this process and relevance in patients are unknown. We aimed to explore the mechanism involved in the abnormal chemotaxis of CXCL12 in several mouse models of NASH and the relevance in the context of human non-alcoholic fatty liver disease (NAFLD). We assessed chemotactic responsiveness of CD4+ T cells to CXCL12, the effect of AMD3100, a CXCR4 antagonist, in mice and lymphocytes from patients with NAFLD, and the affinity of CXCL12 for CXCR4. CXCL12-promoted migration of CD4+ T cells from 3 different mouse models of NASH was increased and dependent of CXCR4. CD4+ T cells from patients with NASH, but not from patients with pure steatosis, responded more strongly to the chemotactic effect of CXCL12, and this response was inhibited by AMD3100. Treatment with AMD3100 decreased the number of CD4+ T cells to the liver in ob/ob mice. CXCL12 expression in the liver, CXCR4 and CXCR7 expression in CD4+ T cells were not increased in 3 different mouse models of NASH. However, the affinity of CXCL12 for CXCR4 was increased in CD4+ T cells of ob/ob mice. In conclusion, the CXCL12/CXCR4 pathway contributes in both mice and patients to the enhanced recruitment of CD4+ T in NASH. An increased affinity of CXCL12 to CXCR4 rather than a higher expression of the chemokine or its receptors is involved in this process.
    Clinical science (London, England : 1979). 07/2014;
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    ABSTRACT: Severe obesity and metabolic syndrome have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). We evaluated the diagnostic value of liver stiffness measurement (LSM), by transient elastography (FibroScan®) in bariatric surgery candidates with suspected NAFLD.
    Obesity surgery. 05/2014;
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    ABSTRACT: Background & aimsPatients with alcoholic liver disease (ALD) display inflammation of the subcutaneous adipose tissue (SAT) which correlates with liver lesions. We examined macrophage markers and polarization in the SAT of alcoholic patients and adipokine expression according to liver inflammation; we studied the consequences of alcohol withdrawal.Patients and methodsForty-seven patients with ALD were prospectively included. SAT and blood samples were collected at inclusion and after one week of alcohol withdrawal. Proinflammatory cytokines/chemokines, inflammasome components and products, adipokine expression levels, macrophage markers and polarization in liver and SAT samples were assessed by RT-PCR arrays.ResultsmRNA expression level of chemokines (IL8, semaphorin 7A) correlated with hepatic steatosis in both liver and SAT. Liver expression of inflammasome components (IL1β, IL18, caspase-1) and SAT IL6 and CCL2 correlated with liver damage. In patients with mild ALD, one week of alcohol withdrawal was sufficient to decrease expression level of total macrophage markers in the adipose tissue, to orient adipose tissue macrophages (ATM) towards an anti-inflammatory M2 phenotype and to decrease the mRNA expression of cytokines/chemokines (IL18, CCL2, osteopontin, semaphorin 7A). In patients with severe ALD, one week of abstinence was also associated with an increase of CCL18 expression.Conclusions In alcoholic patients, upregulation of chemotactic factors in the liver and SAT is an early event that begins as early as the steatosis stage. The inflammasome pathway is upregulated in the liver of patients with ALD. One week of alcohol withdrawal alleviates macrophage infiltration in SAT and orients ATM towards a M2 anti-inflammatory phenotype; this implicates alcohol in adipose tissue inflammation (ClinicalTrials.gov NCT00388323).This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 04/2014; · 3.87 Impact Factor
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    ABSTRACT: The PGAA index was one of the first composite liver fibrosis markers. This study aims, prospectively, to confirm the diagnostic value of PGAA and Fibrotest in patients with alcoholic liver disease and to compare their diagnostic performances. We prospectively included 200 consecutive patients (159 men and 41 women; mean age: 51±0.7 years).The PGAA index was calculated by combining the results of four laboratory tests (prothrombin time, γ-glutamyl transpeptidase, apolipoprotein A1, and α-2-macroglobulin) scored on a 0-4 scale. The Fibrotest score was computed using the Biopredictive website. The overall diagnostic performances of scores were evaluated in terms of the area under the receiver operating characteristic (AUROC) curve. The Obuchowski measure was assessed taking into account the distribution of fibrosis stages observed in the cohort. For predicting F≥2 fibrosis stage, the AUROC curves of PGAA and Fibrotest were 0.83±0.03 and 0.80±0.03, respectively. For predicting F4 fibrosis stage, the AUROC curves of PGAA and Fibrotest were 0.87±0.03 and 0.86±0.03. There was no difference between the AUROC curves of PGAA and Fibrotest. The Obuchowski measure was 0.92±0.01 for PGAA and Fibrotest. For a value of 10, PGAA had 98% specificity and 97% positive predictive value for the detection of F≥2 fibrosis stage and 80% sensitivity and 92% negative predictive value for F4 stage fibrosis. We confirm the comparable diagnostic values of Fibrotest and PGAA. When Fibrotest use is constrained by an increase in unconjugated bilirubin or is not financially viable, PGAA may be an alternative.
    European journal of gastroenterology & hepatology 02/2014; · 1.66 Impact Factor
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    ABSTRACT: Introduction Liver surgery was one of the last fields to be conquered by laparoscopy, which has become safe and effective, especially for left lateral sectionectomy (LLS) and limited peripheral resections. However, major hepatectomies remain challenging. Laparoendoscopic Single-Site (LESS) surgery is being employed for an increasing variety of surgical sites and indications. Presentation of cases Three patients underwent LESS hepatectomy. A 36-year-old woman had LLS for a 38-mm adenoma, an 85-year-old woman an atypical resection of segment VI for a 12-mm hepatocellular carcinoma and a 41-year-old woman an atypical right anterior resection for a 9-cm symptomatic FNH. Procedures were performed transperitoneally with a single-port device, via a 20-mm or 30-mm incision. Operative times were 110 min for LLS, 100 min for the atypical segment VI resection and 120 min for the atypical right anterior liver resection. Blood loss was less than 50 ml in the first two patients and 150 ml in the third. Postoperative courses were uneventful. The first two patients were discharged on postoperative day 3 and the third on postoperative day 1. Discussion To date, some case reports and series of LESS liver surgery have been published. We performed the reported hepatectomies after a considerable experience in laparoscopic hepatic surgery and after applying the LESS approach to other procedures. Our hepatectomy technique was not modified by the use of the single-port and results were very encouraging. Conclusions We believe that in selected patients, both peripheral resections and LLS are feasible by LESS surgery, with good intra-operative and post-operative results.
    International Journal of Surgery Case Reports. 01/2014;
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    ABSTRACT: OBJECTIVE Antidepressant drugs can cause drug-induced liver injury (DILI). The authors review clinical data relevant to antidepressant-induced liver injury and provide recommendations for clinical practice. METHOD A PubMed search was conducted for publications from 1965 onward related to antidepressant-induced liver injury. The search terms were "liver injury," "liver failure," "DILI," "hepatitis," "hepatotoxicity," "cholestasis," and "aminotransferase," cross-referenced with "antidepressant." RESULTS Although data on antidepressant-induced liver injury are scarce, 0.5%-3% of patients treated with antidepressants may develop asymptomatic mild elevation of serum aminotransferase levels. All antidepressants can induce hepatotoxicity, especially in elderly patients and those with polypharmacy. Liver damage is in most cases idiosyncratic and unpredictable, and it is generally unrelated to drug dosage. The interval between treatment initiation and onset of liver injury is generally between several days and 6 months. Life-threatening antidepressant-induced liver injury has been described involving fulminant liver failure or death. The underlying lesions are often of the hepatocellular type and less frequently of the cholestatic and mixed types. The antidepressants associated with greater risks of hepatotoxicity are iproniazid, nefazodone, phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine. The antidepressants that seem to have the least potential for hepatotoxicity are citalopram, escitalopram, paroxetine, and fluvoxamine. Cross-toxicity has been described, mainly for tricyclic and tetracyclic antidepressants. CONCLUSIONS Although an infrequent event, DILI from antidepressant drugs may be irreversible, and clinicians should be aware of it. Aminotransferase surveillance is the most useful tool for detecting DILI, and prompt discontinuation of the drug responsible is essential. The results of antidepressant liver toxicity in all phases of clinical trials should be available and published. Further research is needed before any new and rigorously founded recommendations can be made.
    American Journal of Psychiatry 12/2013; · 14.72 Impact Factor
  • Journal of Hepatology 04/2013; · 9.86 Impact Factor
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    ABSTRACT: Selective control of vascular inflow can reduce blood loss and transfusion rates and may be particularly efficient in laparoscopic liver resection (LLR). The aim of this study was to evaluate the efficacy of selective prior vascular control (PVC) in patients undergoing laparoscopic or open liver resections (OLR). Between 1999 and 2008, 52 patients underwent LLR with PVC with prospective data collection and were compared with patients undergoing OLR with PVC. There was no difference in the operative time between the 2 groups. Blood loss and transfusion rates were lower in patients who underwent LLR (367 vs 589 mL, P = .001; 3.8% vs 17.3%, P = .05, respectively). Morbidity did not differ significantly between the 2 groups. Hospital stay was longer in the OLR group (11.0 vs 7.4 days, P = .001). PVC during LLR was feasible and improved intraoperative and postoperative results. Selective PVC should be obtained in LLR whenever possible.
    American journal of surgery 01/2013; 205(1):8-14. · 2.36 Impact Factor
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    ABSTRACT: OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is prevalent among obese people and is considered the hepatic manifestation of metabolic syndrome. However, not all obese individuals develop NAFLD. Our objective was to demonstrate the role of the gut microbiota in NAFLD development using transplantation experiments in mice. DESIGN: Two donor C57BL/6J mice were selected on the basis of their responses to a high-fat diet (HFD). Although both mice displayed similar body weight gain, one mouse, called the 'responder', developed hyperglycaemia and had a high plasma concentration of pro-inflammatory cytokines. The other, called a 'non-responder', was normoglycaemic and had a lower level of systemic inflammation. Germ-free mice were colonised with intestinal microbiota from either the responder or the non-responder and then fed the same HFD. RESULTS: Mice that received microbiota from different donors developed comparable obesity on the HFD. The responder-receiver (RR) group developed fasting hyperglycaemia and insulinaemia, whereas the non-responder-receiver (NRR) group remained normoglycaemic. In contrast to NRR mice, RR mice developed hepatic macrovesicular steatosis, which was confirmed by a higher liver concentration of triglycerides and increased expression of genes involved in de-novo lipogenesis. Pyrosequencing of the 16S ribosomal RNA genes revealed that RR and NRR mice had distinct gut microbiota including differences at the phylum, genera and species levels. CONCLUSIONS: Differences in microbiota composition can determine response to a HFD in mice. These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity.
    Gut 11/2012; · 10.73 Impact Factor
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    ABSTRACT: BACKGROUND: Only a small proportion of alcoholic patients develop advanced liver disease, suggesting that factors other than alcohol intake may influence alcoholic liver disease (ALD) progression. We have shown that body mass index (BMI) is an independent risk factor for fibrosis in alcohol-induced liver disease and that adipose tissue inflammation is correlated with liver lesions in alcoholic patients. The aim of this study was to determine whether visceral adipose tissue, as assessed by abdominal height measurement, affected individual susceptibility to fibrosis in alcoholic patients. METHODS: We included 127 consecutive alcoholic patients with abnormal liver test findings for whom liver histology data were available. Abdominal height was measured with a Holtain-Kahn abdominal caliper. We carried out univariate comparisons followed by multivariate regression analysis, to investigate the relationship between abdominal height and fibrosis score. RESULTS: Abdominal height (p < 0.005), waist circumference (p < 0.05), fasting blood glucose concentration (p < 0.05), serum triglyceride concentration (p < 0.05), serum bilirubin (p < 0.005), and BMI (p = 0.05) were higher, whereas high-density lipoprotein (HDL) cholesterol level (p < 0.01) was lower in the 72 patients with significant (F2-F4) fibrosis than in the 55 patients with F0-F1 fibrosis. In multivariate regression analysis, only abdominal height (β = 7.2, p < 0.002) was independently and positively correlated with fibrosis score, which was also negatively correlated with HDL cholesterol level (β = -1.04, p < 0.05). CONCLUSIONS: We provide the first demonstration that abdominal height may be a predictor of significant fibrosis in patients with ALD. Our findings support a role for visceral fat accumulation, independent of BMI and of metabolic syndrome criteria, in the onset of alcoholic liver damage.
    Alcoholism Clinical and Experimental Research 09/2012; · 3.42 Impact Factor
  • Cosmin S Voican, Sylvie Naveau, Gabriel Perlemuter
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    ABSTRACT: Thrombocytopenia is a common finding in patients with chronic liver disease related to hepatitis C virus (HCV) infection. Interferon therapy may aggravate thrombopenia through the inhibition of platelet production, leading to premature discontinuation of therapy, dose reduction, and viral relapse. The use of thrombopoietin agonists (romiplostim and eltrombopag) seem to be a useful way to increase the platelet count and facilitate interferon therapy in patients with a chronic HCV infection. Here, we report on the first two cases of patients with HCV-related cirrhosis successfully treated for HCV infection following an increase in the platelet count with romiplostim. Severe thrombocytopenia developed in both patients at weeks 22 and 12 of antiviral therapy, respectively. Considering the risk of relapse in the case of interferon dose reduction or early treatment discontinuation, we initiated platelet growth factor therapy with romiplostim. This approach allowed us to maintain a reasonable platelet count (>50×10/l) and completion of an anti-HCV protocol without dose reduction, achieving a sustained virological response.
    European journal of gastroenterology & hepatology 08/2012; · 1.66 Impact Factor
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    ABSTRACT: Defective hepatitis B virus (dHBV) generated from spliced RNA is detected in the sera of HBV-chronic carriers. Our study was designed to determine whether the proportion of dHBV changed during the course of infection, and to investigate whether dHBV might interfere with HBV replication. To achieve this, HBV wild-type and dHBV levels were determined by Q-PCR in sera from 56 untreated chronic patients and 23 acute patients, in sequential samples from 4 treated-patients and from liver-humanized mice after HBV infection. The proportion of dHBV was higher in patients with severe compared to null/moderate liver disease or with acute infection. Follow-up showed that the proportion of dHBV increased during disease progression. By contrast, a low and stable proportion of dHBV was observed in the humanized-mouse model of HBV infection. Our results highlight a regulation of the proportion of dHBV during liver disease progression that is independent of interference with viral replication.
    Virology 06/2012; 431(1-2):21-8. · 3.35 Impact Factor
  • EASL2012, The Liver Congress, Barcelona; 04/2012
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    ABSTRACT: Most studies on non-alcoholic fatty liver disease (NAFLD) originate from tertiary care centers with an academic interest. How this emerging entity is accepted and managed by a wider body of gastroenterologists is unknown, despite significant implications for the diagnosis of at-risk subjects and the utilization of healthcare resources. We conducted a survey among 352 French, board-certified gastroenterologists from a large variety of practices to understand the clinical burden, perceived severity, and management patterns of NAFLD. Half of participants saw >30 new cases (equal to HCV) of NAFLD and 40% >5 new cases of NASH-cirrhosis yearly. Only 20% of patients were referred by endocrinologists; conversely, gastroenterologists overwhelmingly referred NAFLD patients for assessment of metabolic co-morbidities. In patients with metabolic risk factors, a majority of physicians considered the diagnosis of NAFLD, even if other liver diseases co-existed. The diagnosis heavily relies on aminotransferases, hence patients with normal ALT are usually not diagnosed. Liver biopsy is performed for fibrosis staging but not for the diagnosis/grading of steatohepatitis, and mainly decided based on non-invasive fibrosis procedures. Pharmacological treatment is used despite a lack of clear evidence of efficacy. Physicians monitor patients themselves, usually twice a year. NAFLD is recognized and accepted as a disease in itself with potentially severe outcomes. Most at-risk patients are currently missed because of non-referral by endocrinologists and no exploration of those with normal aminotransferases. The medical need for the diagnosis and treatment of NAFLD is real in the community of gastroenterologists at large.
    Journal of Hepatology 04/2012; 57(2):376-83. · 9.86 Impact Factor
  • EASL2012, The Liver Congress; 04/2012
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    ABSTRACT: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis associated with liver inflammation. Steatosis causes recruitment of lymphocytes into the liver and this is worsened by lipopolysaccharides (LPS). As macrophages may be involved in the lymphocyte homing, we studied the role of lipids in determining the phenotype of Kupffer cells (KCs) at the stage of steatosis. Steatosis was induced in mice by a high fat diet. The turnover and the recruitment of KCs were analyzed in vivo by flow cytometry. KCs phenotype was assessed by optical and electron microscopy, cell culture and lymphocyte recruitment by in vitro chemotaxis. Lipidomic analysis was carried out by mass-spectrometry and gene expression analysis by TaqMan low density array. Although the number of KCs was not modified in steatotic livers compared to normal livers, their phenotypes were different. Electron microscopy demonstrated that the KCs from fatty livers were enlarged and loaded with lipid droplets. Lipid synthesis and trafficking were dysregulated in fat-laden KCs and toxic lipids accumulated. Fat-laden KCs recruited more CD4+ T and B lymphocytes in response to LPS stimulation than did control KCs and produced high levels of pro-inflammatory cytokines/chemokines, which could be reversed by inhibition of lipogenesis. Lipid accumulation in fat-laden KCs is due to a dysregulation of lipid metabolism and trafficking. Fat-laden KCs are "primed" to recruit lymphocytes and exhibit a pro-inflammatory phenotype, which is reversible with inhibition of lipogenesis.
    Journal of Hepatology 03/2012; 57(1):141-9. · 9.86 Impact Factor
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    ABSTRACT: Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis. OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFβ expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F ≥ 2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F ≥ 2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury. OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.
    PLoS ONE 01/2012; 7(4):e35612. · 3.53 Impact Factor
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    ABSTRACT: Quantification of gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) requires normalization to an endogenous reference gene termed housekeeping gene (HKG). Many of the commonly used HKGs are regulated and vary under experimental conditions and disease stages. Alcoholic liver disease (ALD) is associated with several different liver histological lesions that may modulate HKG expression. We investigated the variability of commonly used HGKs (18S, β-actin, glyceraldehyde-3-phosphate [GAPDH], and arginine/serine-rich splicing factor [SFRS4]) in the liver of patients with ALD. Fifty consecutive patients at different stages of ALD underwent liver biopsy. The stability of HKG was assessed according to liver histological lesions. β-actin had the highest coefficient of dispersion (COD) (23.9). β-actin tended to decrease with steatosis and to increase with alcoholic hepatitis; β-actin also increased in patients with both alcoholic hepatitis and cirrhosis. GAPDH and SFRS4 COD were 2.8 and 2.1, respectively. GAPDH was decreased with steatosis and increased with alcoholic hepatitis and fibrosis. 18S had the lowest COD (1.4). Both 18S and SFRS4 levels were not significantly modified with respect to all alcohol-induced liver histological lesions. In patients with ALD, the most constantly expressed HKGs are 18S and SFRS4. These genes are appropriate reference genes for normalization of RT-qPCR in the liver of patients with ALD. The use of other HKGs such as β-actin or GAPDH would lead to misinterpretation of the results.
    Alcoholism Clinical and Experimental Research 09/2011; 36(2):258-66. · 3.42 Impact Factor
  • Cosmin Sebastian Voican, Gabriel Perlemuter, Sylvie Naveau
    Gastroentérologie Clinique et Biologique 06/2011; 35(6-7):465-74. · 0.80 Impact Factor
  • Cosmin Sebastian Voican, Gabriel Perlemuter
    Journal of Hepatology 02/2011; 54(2):388-91. · 9.86 Impact Factor

Publication Stats

1k Citations
336.46 Total Impact Points

Institutions

  • 2007–2014
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2006–2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2005–2013
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2012
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Groupe Hospitalier Saint Vincent
      Strasburg, Alsace, France
  • 2008–2011
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2002–2004
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1999
    • Hôpital Cochin (Hôpitaux Universitaires Paris Centre)
      Lutetia Parisorum, Île-de-France, France