Paul Fortun

Nonsteroidal antiinflammatory drugs and the small intestine.

Purpose of review The small intestine is a more common site for nonsteroidal antiinflammatory drug (NSAID) toxicity than the well-recognized effects on the stomach and duodenum. Although NSAID strictures and perforation are rare, two thirds of regular NSAID users may be prone to small bowel enteropathy. This review highlights this emerging issue in patients requiring antiinflammatory drugs. Recent findings NSAID enteropathy is a stepwise process involving direct mucosal toxicity, mitochondrial damage, breakdown of intercellular integrity, enterohepatic recirculation, and neutrophil activation by luminal contents, including bacteria. Unlike upper gastrointestinal toxicity, cyclooxygenase-mediated mechanisms are probably less important. Newer imaging modalities such as capsule endoscopy studies suggest that small bowel erosions may be common in nonselective NSAID users. Sulfasalazine and metronidazole may prove to be useful, therapeutic options for patients who cannot cease their NSAIDs. Summary NSAID toxicity to the small intestine is common. Useful research tools have been developed to measure intestinal inflammation and permeability indirectly, but these are not generally available to the clinician, although enteroscopy and capsule endoscopy may be helpful. Anemia or hypoalbuminemia are useful clues to NSAID enteropathy. Cessation of the drug is ideal; otherwise, there is experimental data to support the use of sulfasalazine and metronidazole. Animal models are unraveling new mechanisms for mucosal toxicity beyond the yclooxygenase model.

Narrow-band imaging with magnification in Barrett's esophagus: validation of a simplified grading system of mucosal morphology patterns against histology.

BACKGROUND AND STUDY AIMS Validation of a simplified classification of mucosal morphology in prediction of histology in Barretts esophagus using narrow-band imaging with magnification (NBI-Z) and assessing its reproducibility by endoscopists experienced in the use of NBI (NBI-experts) and by endoscopists who were new to NBI (non-NBI-experts). PATIENTS AND METHODS In a prospective cohort study of 109 patients with Barretts esophagus at a single tertiary referral center, mucosal patterns visualized in Barretts esophagus on NBI-Z were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI-Z grading was compared with the final histopathological diagnosis, and positive (PPV) and negative predictive values (NPV) were calculated. The reproducibility of the grading was then assessed by NBI-expert and non-NBI-expert endoscopists, and interobserver and intraobserver agreement were calculated using kappa statistics. RESULTS Per-biopsy analysis: In 903 out of 1021 distinct areas (87.9%) the NBI-Z grading corresponded to the histological diagnosis. Per-patient analysis: The PPV and NPV for type A pattern (columnar mucosa without intestinal metaplasia) were 100% and 97% respectively; for types B and C (intestinal metaplasia) they were 88% and 91% respectively, and for type D (high-grade dysplasia) 81% and 99% respectively. Inter- and intraobserver agreement: The mean kappa values in assessing the various patterns were 0.71 and 0.87 in the non-expert group; 0.78 and 0.91 in the expert group. CONCLUSIONS This study has validated a simplified classification of the various morphologic patterns visualized in Barretts esophagus and confirmed its reproducibility when used by NBI-expert and non-NBI-expert endoscopists.

Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding?

Background:  A 15‐fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non‐steroidal anti‐inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people.

Less Small-Bowel Injury With Lumiracoxib Compared With Naproxen Plus Omeprazole

BACKGROUND & AIMS The selective cyclooxygenase-2 inhibitor lumiracoxib has been shown to reduce endoscopically detected ulcers and ulcer complications in the upper gastrointestinal tract compared with nonselective nonsteroidal anti-inflammatory drugs. We investigated whether lumiracoxib would reduce small-bowel injury compared with naproxen plus omeprazole. METHODS Healthy volunteers were randomized to receive lumiracoxib 100 mg once daily, naproxen 500 mg twice daily plus omeprazole 20 mg once daily, or placebo in a 16-day double-blind, parallel-group study. Small-bowel mucosal injury and inflammation were assessed by video capsule endoscopy, the lactulose:L-rhamnose permeability assessment, and the fecal calprotectin test. RESULTS Of 152 randomized subjects, 139 completed the study with valid video capsule endoscopies (lumiracoxib, n = 47; naproxen plus omeprazole, n = 45; placebo, n = 47). Compared with placebo, an increased number of subjects on naproxen plus omeprazole had small-bowel mucosal breaks (77.8% vs 40.4%, P < .001), with increased permeability (P = .023) and increased fecal calprotectin (increase, 96.8 vs 14.5 mg/kg for placebo; P < .001). With lumiracoxib, 27.7% of subjects had small-bowel mucosal breaks (P = .196 vs placebo; P < .001 vs naproxen), there was no increase in permeability (P = .157 vs placebo; P = .364 vs naproxen), and no increase in fecal calprotectin (-5.7 mg/kg; P = .377 vs placebo; P < .001 vs naproxen). CONCLUSIONS As assessed by 3 different measures, acute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.

Recall of informed consent information by healthy volunteers in clinical trials.

BACKGROUND Information sheets for clinical research are becoming increasingly complex but the extent to which they are understood is uncertain. AIMS To assess, as our primary outcome, recall by healthy volunteers of key facts in a patient information sheet in a phase 3 clinical trial. As secondary outcomes, we examined whether there was a difference between medical student and non-medically trained volunteers. DESIGN Questionnaire to determine recall by healthy volunteers of informed consent information. METHODS Eighty-two healthy volunteers participating in a capsule endoscopy study were given a 13 page written information sheet and allowed to asked questions. After indicating they were ready to give consent they were asked to complete a 6-item questionnaire covering the identity and adverse effects of trial treatments and of the procedure, the duration of the trial and value of the inconvenience allowance. RESULTS All 82 healthy volunteers were questioned. Of the volunteers, 74 (90%) had university level education and 49 (60%) were clinical medical students. However, only 10 subjects (12%) could name the three trial drugs. The maximum number of risks remembered was 6 (n = 2) of 23. Only 14 (17%) could name three or more potential risks of the medication they might be exposed to, whilst 17 (20%) could identify none. Most subjects (77/82, 90%) identified capsule endoscopy as the trial procedure and impaction/obstruction as its main risk (52/82, 64%). All but one subject (98.8%) could recall the exact value of the inconvenience payment. CONCLUSION A comprehensive information sheet resulted in limited recall of trial risks. Shorter information sheets with a test and feedback session should be trialled so that informed consent becomes valid informed consent.

Comparison of high-resolution magnification narrow-band imaging and white-light endoscopy in the prediction of histology in Barrett's oesophagus

Objective. To evaluate whether there is any appreciable difference in imaging characteristics between high-resolution magnification white-light endoscopy (WLE-Z) and narrow-band imaging (NBI-Z) in Barretts oesophagus (BE) and if this translates into superior prediction of histology. Material and methods. This was a prospective single-centre study involving 21 patients (75 areas, corresponding NBI-Z and WLE-Z images) with BE. Mucosal patterns (pit pattern and microvascular morphology) were evaluated for their image quality on a visual analogue scale (VAS) of 1–10 by five expert endoscopists. The endoscopists then predicted mucosal morphology based on four subtypes which can be visualized in BE. Type A: round pits, regular microvasculature; type B: villous/ridge pits, regular microvasculature; type C: absent pits, regular microvasculature; type D: distorted pits, irregular microvasculature. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were then compared with the final histopathological analysis and the interobserver variability calculated. Results. The overall pit and microvasculature quality was significantly higher for NBI-Z, pit: NBI-Z=6, WLE-Z=4.5, p<0.001; microvasculature: NBI-Z=7.3, WLE-Z=4.9, p<0.001. This translated into a superior prediction of histology (Sn: NBI-Z: 88.9, WLE-Z: 71.9, p<0.001). For the prediction of dysplasia, NBI-Z was superior to WLE-Z (χ2=10.3, p<0.05). The overall kappa agreement among the five endoscopists for NBI-Z and WLE-Z, respectively, was 0.59 and 0.31 (p<0.001). Conclusions. NBI-Z is superior to WLE-Z in the prediction of histology in BE, with good reproducibility. This novel imaging modality could be an important tool for surveillance of patients with BE.

The role of stem cell transplantation in inflammatory bowel disease.

Observations that patients undergoing bone marrow transplantation for other disease experienced improvement and sometimes complete remission of their Crohn’s disease (CD) has culminated in exciting programs offering haematopoietic stem cell transplantation (HSCT) as a potential for cure in CD. This article will discuss the concept of inflammatory bowel disease (IBD) as an autoimmune disease (AID), the rationale for HSCT as therapy and review the results so far. We will concentrate largely on CD where most of the therapeutic trials have understandably been aimed, given that ulcerative colitis (UC) has a relatively straightforward cure with surgery.

Cyclooxygenase-2 inhibitors

Purpose of review The purpose of this review is to summarize new information regarding the use of selective inhibitors of the cyclooxygenase-2 enzyme, emphasizing recent developments regarding cardiovascular risk. Recent findings Selective cyclooxygenase-2 inhibitors are as effective as nonselective nonsteroidal antiinflammatory drugs in relieving pain and inflammation but are associated with significantly fewer gastric, duodenal, and intestinal ulcers and ulcer complications. Cyclooxygenase-2 inhibitors may also reduce colorectal polyp development or recurrence as well as reduce the risk of colorectal and esophageal cancer. Some, but not all, studies have suggested increased myocardial infarction with certain cyclooxygenase-2 inhibitors, in particular rofecoxib. It is unclear whether this is a class effect because there are inconclusive data to incriminate celecoxib despite a relatively large number of clinical trials enrolling a large number of patients. Rofecoxib was voluntarily withdrawn by the manufacturer. The European Medicines Agency concluded that cyclooxygenase-2 inhibitors are contraindicated in patients with established cardiovascular disease, should be used with caution in patients with risk factors, and were justified in patients at risk for serious gastrointestinal adverse events. Summary Rofecoxib, but perhaps not all cyclooxygenase-2 inhibitors, may be associated with increased risk for myocardial infarction. It is unclear whether nonselective nonsteroidal antiinflammatory drugs increase or decrease the rate of myocardial infarction. The final truth awaits further studies.

Nonsteroidal antiinflammatory drugs and the small intestine

Purpose of reviewThe small intestine may be a more common site for nonsteroidal antiinflammatory drug toxicity than the gastroduodenal mucosa. Two-thirds of regular nonsteroidal antiinflammatory drug users develop subclinical small bowel enteropathy. This review highlights this emerging issue in patients requiring antiinflammatory drugs. Recent findingsNonsteroidal antiinflammatory drug enteropathy is a stepwise process involving direct mucosal toxicity, mitochondrial damage, breakdown of intercellular integrity, enterohepatic recirculation and neutrophil activation by luminal contents including bacteria. Unlike upper gastrointestinal toxicity, cyclooxygenase-mediated mechanisms are probably less important. Newer imaging modalities such as capsule endoscopy studies demonstrate nonsteroidal antiinflammatory drug-induced small bowel erosions, but the clinical implications are unclear. SummaryNonsteroidal antiinflammatory drug toxicity to the small intestine is common. Useful research tools have been developed to indirectly measure intestinal inflammation and permeability, but these are not generally available to the clinician, although enteroscopy and capsule endoscopy can be illuminating. Anaemia or hypoalbuminaemia are useful indications of nonsteroidal antiinflammatory drug enteropathy. Cessation of the drug would be the preferred option, alternatively there are experimental data to support the use of sulphasalazine and metronidazole. Animal models are unravelling new mechanisms for mucosal toxicity beyond the cyclooxygenase model, including mucosal oxidative injury and nitric oxide mediated pathways.

Gastrointestinal: Early endoscopic findings in watermelon stomach identified by the magnifying endoscopy‐adaptive IHb color enhancement technique

Gastric antral vascular ectasia, or watermelon stomach, is an important cause of chronic blood loss. The majority of patients have antral disease with raised convoluted ridges radiating from the pylorus covered by ectatic vascular tissue. Other patterns include lesions arranged in radiating flat stripes, scattered mucosal lesions, or a mixture of the above types. No data exist in the literature about endoscopic features of watermelon stomach in its mild or early forms. Recently, a method to quantify the content of hemoglobin (Index of Hemoglobin; IHb) has been developed using electronic endoscopic image data. Using a magnifying endoscope and a new image processing technique called ‘adaptive IHb color enhancement’, Yao et al. were able to observe the gastric mucosal microvasculature in detail. When IHb color enhancement is applied to capillary images, the capillary network becomes much clearer. This new technique features an algorithm that increases the redness of mucosa when the hemoglobin content is high, but decreases the redness when the hemoglobin content is low. An elderly female patient was referred to our unit for evaluation of iron deficiency anemia refractory to iron replacement therapy. She had previously undergone extensive gastrointestinal investigations but the only abnormality was antral ‘gastritis’. Antral changes were confirmed by the endoscopic appearance at repeat upper gastrointestinal endoscopy. Using the Olympus GIF-Q240Z magnifying endoscope (Fig. 1) and EVIS LUCERA CV-260 processor with IHb color enhancement (Fig. 2), we were able to visualize dilated telangiectatic capillaries and petechial hemorrhages as typically seen in the watermelon stomach. The patient was treated with argon plasma coagulation and remains well with no further blood loss. The IHb color enhancement technique may permit the detection of early endoscopic features of watermelon stomach.