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Poynard T.,University Pierre and Marie Curie | De Ledinghen V.,Bordeaux University Hospital Center | Zarski J.P.,Clinique University dHepato Gastroenterologie | Stanciu C.,Gastroenterology and Hepatology Institute | And 8 more authors.
Journal of Hepatology | Year: 2012

Background & Aims: Liver fibrosis stage is traditionally assessed with biopsy, an imperfect gold standard. Two widely used techniques, FibroTest®, and liver stiffness measurement (LSM) using Fibroscan® have been validated using biopsy, and therefore the true performances of these estimates are still unknown in the absence of a perfect reference. The aim was to assess the relative accuracy of FibroTest, LSM, and biopsy using methods without gold standard in patients with chronic hepatitis C (CHC) and controls. Methods: A total of 1289 patients with CHC and 604 healthy volunteers, with assessment of fibrosis stage by the three techniques, and alanine aminotransferase (ALT) taken as a control test, were analyzed by latent class method with random effects. In the volunteers, the false positive risk of biopsy was obtained from a large surgical sample of four normal livers. Results: The latent class model with random effects permitted to conciliate the observed data and estimates of test performances. For advanced fibrosis, the specificity/sensitivity was for FibroTest 0.93/0.70, LSM 0.96/0.45, ALT 0.79/0.78 and biopsy 0.67/0.63, and for cirrhosis FibroTest 0.87/0.41, LSM 0.93/0.39, ALT 0.78/0.08 and biopsy 0.95/0.51. The analysis of the discordances between pairs suggested that the variability of the model was mainly related to the discordances between biopsy and LSM (residuals >10; p <0.0001). Conclusions: A method without the use of a gold standard confirmed the accuracy of FibroTest and Fibroscan for the diagnosis of advanced fibrosis and cirrhosis in patients with chronic hepatitis C. The variability of the model was mostly due to the discordances between Fibroscan and biopsy. © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Reddy K.R.,University of Pennsylvania | Shiffman M.L.,Health News | Rodrigueztorres M.,Fundacion de Investigacion de Diego Santurce | Cheinquer H.,Hospital Of Clinicas Of Porto Alegre | And 8 more authors.
Gastroenterology | Year: 2010

Background & Aims Patients infected with hepatitis C virus (HCV) genotype 1, body weight <85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin. Methods This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight <85 kg and HCV RNA titer <400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment. Results Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.831.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.791.28; P = .974). Conclusions In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight <85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen. © 2010 AGA Institute.


PubMed | Liver Unit, Health Science University, Soroka Medical Center, Genaphora Ltd. and 7 more.
Type: | Journal: Antiviral therapy | Year: 2017

Direct-acting antiviral (DAA) treatment regimens and response rates of patients with hepatitis C virus (HCV) genotype 1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions.In a multicenter cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virologic response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virologic failure.GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second- generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations.NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.


PubMed | Rivka Ziv Medical Center, Tel Aviv University and Gastroenterology and Hepatology Institute
Type: | Journal: Clinics and research in hepatology and gastroenterology | Year: 2016

Patients with ulcerative colitis (UC) are prone to colorectal cancer and dysplastic polyps and also have sporadic adenomas. There is scant information, however, relating the prevalence of sporadic adenomas in UC patients compared with normal subjects. The aim of this study was to assess the prevalence of all dysplastic lesions in UC and compare the prevalence of adenomas to that in the general population.A single-center retrospective study, in which all patients with diagnosed UC were followed during a ten-year period. The incidence of polyps and colorectal cancers were recorded and compared to that of an age-matched group in the general population who had screening colonoscopy.A total of 229 UC patients were included compared with 450 age-matched subjects who underwent a single colonoscopy. The average number of colonoscopies per UC patient was 3. The rate of sporadic adenomas among UC patients (9.6%), as well as the rate of all dysplastic polyps (11.2%) in these patients, were significantly lower than the rate of adenomas among the control population (24%; OR 0.33-0.44; P<0.0001). Despite this, the rates of colon cancer were comparable between the groups (2.1% vs. 1.5%, P=0.55).In spite of the observed lower rate of dysplastic polyps in UC patients, this should not preclude tight surveillance in this high-risk population.


PubMed | Bar - Ilan University, Tel Aviv University and Gastroenterology and Hepatology Institute
Type: Journal Article | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2015

Primary sclerosing cholangitis and inflammatory bowel disease are two associated, chronic inflammatory, pre-malignant conditions. We hypothesized that patients with these disorders may harbour telomere dysfunction as a marker of chromosomal instability. The aim of our study was to compare parameters of the telomere-telomerase system in these cohorts.In this prospective study, peripheral blood was withdrawn from patients with primary sclerosing cholangitis (N=20), inflammatory bowel disease (N=20) and healthy controls (N=20), and lymphocytes were isolated. Telomere length was quantified as a function of the signal intensity and telomere number. Random aneuploidy and telomere capture were determined by fluorescence in situ hybridization technique with specific probes.Patients with inflammatory bowel disease had higher measures of intestinal disease activity than patients with primary sclerosing cholangitis. Despite this, shorter telomere length and telomere aggregates, especially the fusion of 2-5 telomeres, were observed at significantly higher rate in patients with primary sclerosing cholangitis relative to inflammatory bowel disease or healthy controls. Rates of aneuploidy and telomere capture were higher in the two probes in both diseases compared to controls (p<0.001).Dysfunction of telomeres was demonstrated in primary sclerosing cholangitis patients more than inflammatory bowel disease and healthy controls patients, which attests to genetic instability and immunosenescence.NCT02247622.


PubMed | Tel Aviv University and Gastroenterology and Hepatology Institute
Type: Journal Article | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2015

The yield of surveillance colonoscopies for patients with a history of polyps is well established for first surveillance, but limited for second surveillance. The aim of this study was to evaluate the proportion of high-risk adenomas at second surveillance colonoscopy based on findings of previous colonoscopies.This retrospective cohort study was conducted in a tertiary hospital and patients who had undergone three colonoscopies were included. Based on the findings at index colonoscopy, patients were categorized into three groups: high-risk adenoma (n=252), low-risk adenoma (n=158) or no-adenoma (n=318). Findings of subsequent high-risk adenoma, low-risk adenoma and no adenoma at surveillance colonoscopies were documented in each group.Among patients with high-risk adenoma at index and first surveillance colonoscopies, significantly higher rates of high-risk findings were found at second surveillance, compared with patients who had low-risk or no-adenoma at index colonoscopy and high-risk adenoma at first surveillance colonoscopy (58%, 33% and 10%, respectively, p<0.001).Both index colonoscopy and first surveillance high-risk adenoma have an impact on incidence high-risk findings at second surveillance colonoscopy and these subjects need close surveillance.


Zigmond E.,Weizmann Institute of Science | Zigmond E.,Gastroenterology and Hepatology Institute | Jung S.,Weizmann Institute of Science
Trends in Immunology | Year: 2013

Macrophages are the most abundant mononuclear phagocytes in the healthy intestinal lamina propria and have emerged as crucial sentinels for the maintenance of tissue homeostasis. Matching the dynamic mucosal landscape, CX3C chemokine receptor (CX3CR)1-expressing macrophages are relatively short lived, and as opposed to most other tissue macrophages, are continuously replaced from blood monocytes that acquire in the healthy tissue context a robust noninflammatory gene expression signature. By contrast, during gut inflammation, monocytes differentiate in the gut into proinflammatory effector cells, as well as migratory antigen-presenting cells. Manipulation of monocyte fates in the intestine might hold promise for the disease management of inflammatory bowel disorders. © 2013 Elsevier Ltd.


Laish I.,Gastroenterology and Hepatology Institute
Harefuah | Year: 2012

Thiopurine drugs, azathioprine (Imuran) and 6-mercaptopurine (6-MP), are immunomodulators that have been shown to be effective at inducing and maintaining remission in inflammatory bowel disease. Although usually well-tolerated, the occurrence of side effects, typically myelotoxicity and hepatotoxicity, is a major drawback. The side effects can be classified as dose-dependent and independent. Both cholestatic hepatitis and endothelial injury, leading to vascular congestion and nodular regenerative hyperplasia, have been described during therapy with thiopurines, which can end up with portal hypertension. These injuries are potentially mediated by different metabolites. In this article we present a case of hyperammonaemic encephalopathy during therapy with 6-MP, possibly the first recorded in the literature, which probably resulted from the combination of thiopurine-induced liver injury with portal hypertension and the presence of spontaneous portosystemic venous shunts.


Bar-On L.,Weizmann Institute of Science | Zigmond E.,Weizmann Institute of Science | Zigmond E.,Gastroenterology and Hepatology Institute | Jung S.,Weizmann Institute of Science
Seminars in Immunology | Year: 2011

Inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis represent a major challenge to clinicians and immunologists trying to understand why in certain individuals the peaceful coexistence of the commensal microflora and its host breaks down and results in chronic inflammation. Here we summarize the recent progress in our understanding of the organization of the intestinal mononuclear phagocytes with dendritic cells and macrophages of distinct phenotype, origin and function. Finally, we discuss potential strategies to translate the recent findings into the management of chronic inflammation in animal models of IBD. © 2011 Elsevier Ltd.


PubMed | Gastroenterology and Hepatology Institute
Type: | Journal: Cytogenetic and genome research | Year: 2016

Nonalcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC) are considered preneoplastic conditions that might progress to hepatocellular carcinoma. We evaluated parameters of telomere dysfunction in these patient groups to study the correlation between telomere length and the progression of NAFLD. We analyzed peripheral lymphocytes from 22 patients with NAFLD, 20 patients with CC, and 20 healthy, age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization, and cellular senescence was evaluated by the percentage of cells with senescence-associated heterochromatin foci. The expression of telomerase reverse transcriptase (hTERT) mRNA was measured using polymerase chain reaction, and telomere capture (TC) was assessed with 2 Cytocell probes, 15qter and 13qter. Shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD, compared to the CC patients and healthy controls. While hTERT mRNA was significantly decreased, TC was increased in CC patients, compared to the NAFLD group and healthy individuals. Thus, there is a correlation between hTERT mRNA expression and telomere length in patients with NAFLD, which might be related to associated metabolic disorders and the risk of malignant transformation. Patients with CC, on the contrary, elongate their telomeres through the TC mechanism.

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