J. Deviere

Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis

Background and aims: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn’s disease (CD) and/or ulcerative colitis (UC). Methods: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios. Results: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28–4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24–4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07–3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately. Conclusion: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.

Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and work-up of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.

Profile of soluble cytokine receptors in Crohn’s disease

Introduction: Soluble cytokine receptors (sCRs) modulate the in vivo activity of cytokines. Deficient sCR production could participate in the pathogenesis and course of Crohn’s disease (CD). The aim of the study was to examine the profile of sCRs in CD patients and their modulation by infliximab and corticosteroids. Methods: We prospectively examined active CD patients (aCD) treated with either infliximab (n = 21) or corticosteroids (n = 9), CD patients in clinical remission (rCD, n = 20), ulcerative colitis patients (UC, n = 24), and healthy subjects (HS, n = 15). Cultures of colonic biopsies were also examined from CD inflamed (n = 8), CD non-inflamed (n = 7), and healthy mucosa (n = 8). Levels of tumour necrosis factor α (TNF-α), soluble TNF receptor I (sTNFRI), soluble TNF receptor II (sTNFRII), interleukin 1β (IL-1β), soluble IL-1 receptor I (sIL-1RI), soluble IL-1 receptor II (sIL-1RII), IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 were measured using ELISA. Results: Higher levels of sTNFRI (p<0.05, p<0.01), sTNFRII (p<0.01, p<0.01), sIL-1RI (p<0.05, NS), IL-6 (p<0.01, p<0.01), and sIL-6R (p<0.05, NS) were observed in aCD compared with rCD and HS. Interestingly, sIL-1RII (p<0.05, p<0.01) and sgp130 (p<0.01, p<0.01) were profoundly decreased in aCD compared with rCD and HS, and were negatively correlated with CRP. Deficient production of sIL-1RII was specific to CD (not observed in ulcerative colitis), and was further confirmed at the mucosal level. Infliximab decreased sTNFRII at one and four weeks (p<0.05) and enhanced sIL-6R levels at one week (p<0.05). Corticosteroids increased sIL-1RII levels at one week (p<0.05). Conclusion: CD is associated with dysregulated production of sCRs. Deficiency in sIL-1RII and sgp130 may be essential to CD pathogenesis. Their replacement through the use of fusion proteins could represent future alternative therapeutic strategies for CD.

Factors related to early mortality in cirrhotic patients bleeding from varices and treated by urgent sclerotherapy.

Variceal haemorrhage in cirrhotic patients carries a high early mortality even when balloon tamponade or emergency sclerotherapy are applied. The aim of this study to identify patients dying within six weeks of their first variceal haemorrhage. One hundred and twenty one patients with parenchymal cirrhosis presenting with the first variceal bleeding episode between June 1983 and December 1988 were studied. Nineteen patients were excluded for various reasons. Emergency sclerotherapy was carried out in cases of active bleeding or where there were endoscopic signs of recent bleeding, and then regularly repeated afterwards. Of the 24 variables studied and included in a multivariate analysis using a logistic regression model, three had an independent prognostic value: encephalopathy, prothrombin time, and the number of blood units transfused within the 72 hours of time zero. The subsequent regression equation was able to predict 89% of the patients who will die and 97% of the patients who will still be alive six weeks after their first variceal haemorrhage treated by sclerotherapy. Pugh score was less discriminatory than these last three variables in terms of accuracy of adjustment, goodness of fit to the model, receiver operating characteristic curves, and percentage correct prediction. To measure the accuracy of the prediction rule, our model was applied to another series of 28 cirrhotic patients admitted with their first variceal bleeding during the next period (January 1989 to May 1990). Death and survival were correctly predicted in respectively 82% and 94% of the cases. The use of this score is recommended for the selection of patients with high early mortality after variceal bleeding despite sclerotherapy, and for the design of new therapeutic trials.

Les complications du drainage biliaire interne endoscopique

RésuméAprès avoir utilisé des prothèses de 5, 6 et 7 French avec un taux de complications de plus de 40 %, il fut possible dès 1981 d’insérer des prothèses de gros calibre grâce aux duodénoscopes Olympus à canal large de 3,7 puis 4,2 mm.La série des auteurs comporte 94 patients traités d’une part à l’aide de prothèses Surgimed de 10 Fr de type Amsterdam et, d’autre part, de prothèses Biotrol de 9 French. 29 patients ont été récemment traités à l’aide de prothèses Biotrol 10 French dont les caractéristiques (forme, diamètre intérieur, orifices de drainage) se sont améliorées sur base des études cliniques et in vitro.Les indications pour cette série de 94 patients ont été le cancer du pancréas (36 cas), le cholangiocarcinome (20 cas), le cancer de la vésicule biliaire (16 cas), des métastases d’autre origine (13 cas), une récidive tumorale après duodéno-pancréatectomie (1 cas). 8 cas seulement concernaient des situations bénignes. La survie moyenne des malades porteurs d’un cancer fut de 134 jours (3–450) et variait selon la localisation de la tumeur. La principale complication précoce est l’angiocholite.Les complications tardives comportent l’obstruction de la prothèse, son déplacement, la cholécystite aiguë, les abcès intrahépatiques, l’abcès pancréatique et la fracture de prothèse. L’analyse des résultats du drainage biliaire interne et l’expérience des différentes complications ainsi que les études expérimentales faites in vitro ont permis de définir les caractéristiques optimales pour les prothèses biliaires et de proposer une attitude thérapeutique rationnelle en cas de complication.SummaryAfter using 5, 6 and 7 French endoprostheses with a 40 % complication rate, it was possible from 1981 onwards to insert large calibre prothesis with the 3.7 and then with the 4.2 mm wide channel Olympus duodenoscope.This study consists of 94 patients treated on the one hand with 10 Fr Amsterdam type Surgimed endoprostheses and, on the other hand with 9 French Biotrol endoprostheses. 29 patients were recently treated with 10 French Biotrol endoprostheses, the characteristics of which (shape, internal diameter, side holes) being improved by clinical and in vitro studies.Our 94 patients include cases of pancreatic carcinoma (36 cases), cholangiocarcinoma (20 cases), carcinoma of the gallbladder (16 cases), metastasis from other sources (13 cases), and tumoral relapse after duodeno-pancreatectomy (1 case). There were only 8 cases of benign strictures.The average survival rate was 134 days (3–450) and varied with the level of the stricture. Cholangitis was the main early complication. Late complications were clogging of the endoprosthesis, its dislodgement, acute cholecystitis, intra-hepatic abscesses, pancreatic abscess and fracture of the endoprosthesis. Analysis of internal biliary drainage results and experience of the different complications as well as experimental in vitro studies has enabled us to define optimal characteristics for biliary endoprostheses and outline a rational therapy when complications arise.

Fatal hemobilia in advanced hepatocellular carcinoma invading biliary tract after treatment with sorafenib and biliary stenting

Sorafenib, a multikinase inhibitor, is now the standard treatment of advanced hepatocellular carcinoma (HCC) [1, 2]. Several clinical studies assessing sorafenib in advanced HCC have shown that it is generally a well-tolerated drug. The main side-effects are gastrointestinal disorders like diarrhoea and hand–foot syndrome [1–3]. No significant increase of hemorrhagic events was observed in cirrhotic patients with advanced HCC treated with sorafenib, even in patients with Child–Pugh B cirrhosis [4]. However, a recent meta-analysis showed a significant two-times increased risk of bleeding events with sorafenib and sunitinib [5]. Most events were of low grade, but some were reported as fatal, mainly in pulmonary neoplasms. In patients with advanced HCC treated with sorafenib, only one bleedingrelated death due to intracranial haemorrhage was reported [3, 5]. We report here for the first time two cases of fatal hemobilia in patients who presented with HCC invading biliary tract and who received sorafenib after optimal endoscopic biliary drainage. These two patients with cirrhosis of liver were admitted to the hospital for jaundice and the radiological investigations including a magnetic resonance imaging cholangiopancreatography revealed hypervascularised tumour, evocating HCC, with tumoural biliary luminal invasion. Aiming to relieve obstructive jaundice, endoscopic retrograde cholangiopancreatographic examinations were carried out for both patients. For patient 1, three plastic stents were placed into the right and left hepatic ducts, and for the second patient, a metallic stent was placed into the common bile duct. Cytologic analysis from biliary brushing was positive for malignant cells in the two cases. After stenting, patients recovered well with Eastern Cooperative Oncology Group performance status 0 and Child B Pugh 7 score due to the persistence of an elevated bilirubin; there were no other abnormalities indicating profound liver function impairment. Sorafenib was started, in both patients 3 weeks after stenting, at the dose of 400 mg twice daily. After sorafenib therapy, both patients were admitted to the emergency unit with hemorrhagic shock on the 7th and 2nd day, respectively. In both cases, upper gastrointestinal endoscopy showed fresh blood emerging from the biliary stent and endoscopic retrograde cholangiopancreatography confirmed the hemobilia. Both patients died of hemorrhagic shock, despite supportive care, transfusion of blood products, endoscopic procedures and attempt at angiographic embolisation. To our knowledge, these are the first reports of fatal uncontrollable hemobilia in patients with advanced HCC treated with a short course of sorafenib. The peculiarity of these two similar cases was the biliary luminal invasion by the tumour (hilar tumour in case 1 and metastatic lymph nodes in case 2) causing obstructive jaundice and requiring endoscopic biliary stenting. In these cases, questions should arise concerning the eventual relationship between sorafenib and bleeding occurring from hypervascular tumours invading the biliary tract. Indeed, the cause and as well as the timing of the observed events clearly indicate a close relationship between sorafenib administration and subsequent hemobilia, despite a short course of treatment. One may also question the additional role of stenting procedures to account for the bleeding episodes. In summary, these two cases raise the question of potential contraindication of sorafenib in advanced HCC with direct involvement of the biliary ducts requiring endoscopic stenting. The safety and dosage of sorafenib in this particular subgroup of advanced HCC patients must be evaluated more widely.

Unexplained digestive bleeding in a cirrhotic patient

A 50 year old White man with cirrhosis due to hepatitis C virus (HCV) infection was admitted to our hospital for severe anaemia and intermittent melena. At admission, haemoglobin was …

The inflammatory cascade of liver ischemia and reperfusion: from the donor to the recipient

The first attempted liver transplantation was reported in 1955 by C. S. Welch, who described the insertion of an auxiliary graft in dogs [1]. Animal liver replacement (orthotopic transplantation) was performed 1 year later by J. Cannon [2]. At that time no immunosuppression was administered and preservation of the graft was not a crucial objective. Hence, results were affected by high rates of rejection and mortality. Improvements in organ preservation and development of immunosuppressive regimens, based on those used in kidney transplantation, prompted pioneering surgeons to transpose animal’s experience to humans. The years 1963 and 1964 saw these first attempts in the United States and Europe [3, 4]. However, none of the patients concerned survived more than 1 month. Therefore, pessimism prevailed world-wide concerning this procedure. Years of laboratory efforts led to a new wave of enthusiasm for human liver transplantation. From 1967 to 1980, several teams began a liver transplantation program but, despite considerable efforts, the resulting 1-year survival rates remained under 50% [5]. Albeit miraculous benefits were obtained, the procedure was considered feasible but impracticable on a large scale given the high mortality rates often occurring during the first postoperative months. Revolution came from the availability of cyclosporine as a new immunosuppressive drug in 1979 [6] and the development of the UW(University of Wisconsin) preservation solution at the end of the 1980s [7].

Prophylactic but not therapeutic administration of N-acetylcysteine (NAC) decreases the severity of experimental acute pancreatitis

Background: Inflammation and oxidative stress occur in the pancreas during the early stages of acute pancreatitis. NAC is a thiol compound and can act as a direct scavenger of reactive oxygen species leading to decrease the inflammatory process. Aim: To assess the prophylactic as well as the therapeutic effect of NAC on the early course of acute necrotizing pancreatitis in mice. Methods: Acute pancreatitis (AP) was induced through 4 i.p. injections of 50 }ag/kg cerulein. Mice were assigned to receive either, Group 1: NAC given orally during one week + 1000 mg/kg i.p. one hour before AP induction then every 3 hours for 2 doses, or Group 2:1000 mg/kg i.p. one hour before AP induction then every 3 hours, or Group 3:1000 mg/kg i.p. one hour after AP induction then every 3 hours or Group 4: only saline before AP induction. Severity of AP was assessed in terms of Serum amylase/lipase levels, histological changes (edema, inflammation, necrosis), systemic release of TNF-a and IL-6, intrapancreatic levels of TNF-a and IL-6 and pancreatic glutathione content. Results: Prophylactic administration of NAC (Groups 1 and 2) dramatically decreased the severity (histologically and amylase/lipase levels at 3 and 6 hours after induction) of AP as compared to Group 3 (therapeutic administration) and Group 4 (controls) whose severity was similar. Interestingly, no significant difference was found between group 1 and 2 (NAC given orally as pretreatment or not). Prophylactic administration of NAC led to a significant decrease of systemic IL-6 release (TNF-ct not detectable in this model) and of intrapancreatic IL-6 and TNF-ct levels as compared to therapeutic administration or controls (3 and 6 hours after induction). However, this effect was not dose-dependent (300 mg/kg i.p. = 600 mg/kg = 1000 mg/kg). No significant differences in total pancreatic gluthatione content were found in mice treated with NAC before AP induction compared with those in mice treated with NAC after induction or with controls. Conclusions: NAC administered only in a prophylactic protocol limits the severity of cerulein-induced AP in mice despite no change on pancreatic glutathione content. This suggests that oxidative stress occurs very early in the course of AP and probably triggers the inflammatory process through cytokines induction. This approach may substantiate the prophylactic use of NAC in preventing post-ERCP pancreatitis.