To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD).
Caecal biopsies were ...collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants.
IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS.
In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.
The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. ...Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.
Abstract In European countries, epidemiology of hepatitis E virus (HEV) infection is not well known. Although, seroprevalence of HEV Immunoglobulin G reached a few percent in European women, no acute ...hepatitis E during pregnancy has been described so far. Here, we report a case of an autochthonous HEV genotype 3 infection in a 41-years-old pregnant woman living in a non-endemic country. The acute hepatitis had a spontaneous good outcome for the mother and the child. In non-endemic areas where Hepatitis E infections are emerging, unexplained cytolysis, whatever its level, in a pregnant woman could be investigated for HEV, using biological molecular and serology tools.
Summary
Background
The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) (“fibrotic NASH”) is becoming an ...important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved.
Aim
To develop a new blood test specifically dedicated for this new diagnostic target of interest.
Methods
Eight Hundred and forty‐six biopsy‐proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets.
Results
The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK‐3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut‐offs were calculated. In the validation set, MACK‐3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut‐offs (36.0% of the patients), MACK‐3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well‐classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%.
Conclusion
The new blood test MACK‐3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved.
Recent evidence suggests a role for increased colonic permeability and mucosal mast cell (MC) mediators on symptoms related to the irritable bowel syndrome (IBS). Whether allergic factors (AFs) are ...involved in the pathophysiology of IBS is unclear. We addressed the question of the possible influence of an allergic background on IBS symptoms.
We assessed paracellular permeability, mucosal MCs counts, and spontaneous release of tryptase of colonic biopsy specimens in 34 IBS patients and 15 healthy subjects. The severity of IBS was assessed through self-reported questionnaires. All individuals were tested for the presence of AF, including self-perception of adverse reaction to food, personal and familial history of atopic disease, elevated total or specific immunoglobulin E against food/inhalant antigens, blood eosinophilia, and skin tests.
IBS patients had significant enhanced colonic permeability, higher number of MCs, and spontaneous release of tryptase than healthy subjects. The severity of IBS was significantly correlated with colonic permeability (r=0.48, P=0.004), MCs counts (r=0.36, P=0.03), and tryptase (r=0.48, P=0.01). In 13 IBS patients (38.2%) having at least three AFs, symptoms scores, colonic permeability, MCs counts, and tryptase release by colonic biopsies were significantly higher than in those with less than three AFs. IBS patients with at least three AFs were more prone to diarrhea or alternating symptoms. None AF was found to be predictive of IBS severity.
In IBS patients, the presence of an allergic background correlates with a more severe disease and diarrhea predominance, possibly by enhancing mucosal MC activation and paracellular permeability.
Aliment Pharmacol Ther 2010; 32: 1315–1322
Summary
Background Non‐invasive approaches are useful to differentiate simple steatosis from non‐alcoholic steatohepatitis (NASH) in obese and morbidly ...obese patients.
Aim To develop a new scoring system to diagnose definitive NASH.
Methods Preoperative clinical and biological data including serum caspase 3‐generated cytokeratin‐18 fragments (CK18) and surgical liver biopsies were obtained from 464 morbidly obese patients who had undergone bariatric surgery. The cohort was divided into two groups: training group (n = 310) and validation group (n = 154). Definitive NASH was defined according to Kleiner’s classification with a Non‐alcoholic fatty liver disease Activity Score (NAS) ≥5.
Results Alanine aminotransferase (ALT), CK18 fragments and the presence of metabolic syndrome were independent predictors for discriminating patients with NAS ≥5 in the training group. These three parameters were used to carry out a scoring system for the prediction of NAS ≥5. Whereas serum CK18 fragment alone had an area under the receiver operating characteristic (AUROC) curve = 0.74, AUROC curves of the scoring system were 0.88 and 0.83 in the training group and the validation group, respectively.
Conclusion A simple and non‐invasive composite model (the Nice Model) including metabolic syndrome, ALT and CK18 fragments is able to predict accurately a non‐alcoholic fatty liver disease activity score ≥5 in morbidly obese subjects.
Aliment Pharmacol Ther 2010; 32: 225–232
Summary
Background Life‐threatening bleeding caused by early spontaneous slippage of rubber bands has been described after variceal ligation in cirrhotic ...patients.
Aim To determine the predictive factors of this complication in cirrhotic patients.
Methods Among 605 patients, 21 patients (mean age 56.6 ± 13.5 years) developed 23 spontaneous band slippages with bleeding on post banding ulcer, as confirmed by endoscopy. Cirrhosis was alcoholic in 13 patients (62%), post viral hepatitis in three (14%) and from other causes in five (24%). A case‐control study was performed comparing 17 from these patients who presented the complication after a first ligation with 84 of the 584 controls who underwent first endoscopic variceal ligation without bleeding complication.
Results Bleeding occurred 13.5 days ± 7.3 (2–29) following ligation. Eleven patients died following the bleeding complication (52%). Using a multivariate analysis, previous upper variceal digestive bleeding OR 12.07, 95%CI (2.3–63.43), peptic oesophagitis OR 8.9, 95%CI (1.65–47.8), high platelet ratio index (APRI) score OR 1.54, 95%CI (1.11–2.16) and low prothrombin index OR 0.54, 95% CI (0.31–0.94) were independent predictive factors of bleeding.
Conclusions Bleeding related to post‐banding ulcer is a rare, but severe complication. The proposed predictive factors should be looked for and minimized before variceal ligation.
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