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Diet May Influence Relapse in Ulcerative Colitis new
      #115476 - 10/24/04 07:50 PM

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Diet May Influence Relapse in Ulcerative Colitis

Laurie Barclay, MD

Sept. 20, 2004 — Potentially modifiable dietary factors, such as high meat or alcoholic beverage intake, may increase the likelihood of relapse for patients with ulcerative colitis (UC), according to the results of a prospective cohort study published in the September issue of Gut.

"The causes of relapses of UC are unknown," write Sarah L. Jowett, MRCP, from the University of Newcastle upon Tyne, U.K., and colleagues. "Dietary factors have been implicated in the pathogenesis of UC."

To determine the effect of customary diet on likelihood of relapse, 191 patients in remission were recruited from two district general hospitals and followed for one year. Relapse was defined using a validated disease activity index; a food frequency questionnaire determined nutrient intake; and multivariate logistic regression, controlling for nondietary factors, determined adjusted odds ratios for relapse.

Of the 191 patients, 96% completed the study, and 52% relapsed. Compared with the lowest tertile of meat consumption, the highest tertile was associated with triple the risk of relapse (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.3 - 7.8. Intake of red and processed meat was an even greater risk factor (OR, 5.19; 95% CI, 2.1 - 12.9. The top tertile of intake for protein (OR, 3.00; 95% CI, 1.25 - 7.19) and alcohol (OR, 2.71; 95% CI, 1.1 - 6.67) also increased the likelihood of relapse, as did high intake of sulfur (OR, 2.76; 95% CI, 1.19 - 6.4) or sulphate (OR, 2.6 (95% CI, 1.08 - 6.3).

Contrary to commonly held beliefs, increased intake of milk or dairy products did not increase risk of relapse, and increased intake of dietary fiber did not appear to protect against relapse.

Study limitations include potential criticisms of the dietary assessment tool; assessment of habitual diet at only one time point for each individual; failure to perform sigmoidoscopy or analysis of stool samples; and incomplete data for sulfur and sulphate content of the diet.

"Potentially modifiable dietary factors, such as a high meat or alcoholic beverage intake, have been identified that are associated with an increased likelihood of relapse for UC patients," the authors write. "Further studies are needed to determine if it is the sulphur compounds within these foods that mediates the likelihood of relapse and if reducing their intake would reduce relapse frequency."

Northumbria Healthcare Trust funded Dr. Jowett.

In an accompanying commentary, Herbert Tilg, from University Hospital Innsbruck in Austria, and Arthur Kaser, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, note that the role of dietary factors in UC relapse may be mediated by hydrogen sulfide production.

"This provocative and clinically important report by Jowett et al reopens the topic of diet and relapsing UC," Drs. Tilg and Kaser write. "The findings are well taken and may offer a new perspective for potential intervention by practical lifestyle modifications, and as such are eagerly awaited by our patients. Despite this excitement, interventional studies are now needed, setting the scene for specific dietary recommendations and for further defining the role of sulphur/sulphate which may even lead to novel therapies."

Gut. 2004;53:1399-1401, 1479-1484

Reviewed by Michael W. Smith, MD

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Increased Incidence of Inflammatory Bowel Disease: The Price of the Decline of Infectious Burden? new
      #125865 - 11/28/04 02:58 PM

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From Current Opinion in Gastroenterology

Increased Incidence of Inflammatory Bowel Disease: The Price of the Decline of Infectious Burden?

Posted 11/11/2004

Hélène Feillet; Jean-François Bach

Abstract and Introduction
Purpose of Review: It is now apparent that the increase in the incidence of autoimmune and allergic diseases in Western countries is explained by the decrease in infections. The question is posed to determine whether a similar explanation can be proposed for the increased incidence of inflammatory bowel disease.
Recent Findings: Studies performed in murine experimental models of inflammatory bowel disease have shown that colitis onset can be prevented by bacteria, bacterial extracts, or helminths. Particular interest was given to probiotics (either live or killed), which protect from disease in a toll-like receptor 9 dependent fashion. This protective effect involves regulatory cytokines as indicated by in vitro studies on human inflamed colonic cells. At the clinical level, there is strong suggestion but still limited proof that probiotics improve inflammatory bowel disease through immunoregulatory mechanisms.
Summary: Converging clinical and experimental data strongly suggest the protective nonspecific role of infections on inflammatory bowel disease independently from the triggering role of some specific bacteria. The extension to inflammatory bowel disease of the hygiene hypothesis opens new therapeutic perspectives including the revisiting of probiotics and other forms of exposure to bacteria or parasite components.

Converging epidemiologic data reveal a steady increase in the incidence of inflammatory bowel disease (IBD) during the last half of the twentieth century, even if a plateau has now been reached in some high-incidence areas such as northern Europe and North America.[1*,2] This increase in incidence is real but should be qualified in terms of the improvement of disease awareness and diagnosis. During the same period, an obvious trend towards the decline of infectious diseases was noted.[3]

As has been previously done for allergic and autoimmune diseases, it was tempting to hypothesize a causal relation between these two observations (according to the hygiene hypothesis). Because of decreased solicitation by infectious agents, the immune system mounts immunopathologic responses against various antigens (autoantigens, allergens, and antigens from some specific pathogens), giving rise to immune disorders.


Hélène Feillet and Jean-François Bach, Necker Hospital, Paris, France

Curr Opin Gastroenterol 20(6):560-564, 2004. © 2004 Lippincott Williams & Wilkins

Section 1 of 7 Next Page: Suggestive Epidemiological Data
To view this whole article, follow the link:

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Probiotics Prove Just As Effective As a Popular Prescription Drug for Ulcerative Colitis new
      #131903 - 12/20/04 01:37 PM

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12.10.04 -- Probiotics Prove Just As Effective As a Popular Prescription Drug for Ulcerative Colitis

By Greg Arnold, DC, CSCS, October 21, 2004, abstracted from "Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine" in the November 2004 issue of Gut

Inflammatory bowel disease (IBD) includes a number of chronic, relapsing inflammatory disorders involving the gastrointestinal tract. It is estimated that more than 600,000 people in the United States have some form of inflammatory bowel disease.1 Classically, inflammatory bowel disease includes ulcerative colitis and Crohn's disease.

Ulcerative colitis (UC) presents as inflammation extending throughout the entire colon. Research increasingly suggests that the inflammation associated with UC and IBD is related to an overabundance of "bad" bacteria and a deficiency of "good bacteria" known as probiotics.(2, 3) Now a new study4 has found probiotics act just as well as prescription drugs in helping relapses in UC.

Researchers studied 327 IBD patients, with 162 receiving 200 mg Escherichia Coli Nissle once daily while 165 received 500 mg mesalazine, a prescription drug regarded as the "gold standard" for treating IBD, three times daily for one year. Patients were assessed were regularly assessed for signs of relapse using the Rachmilewitz clinical and endoscopic activity indices, and according to histology at the end of the study.

Compared to the relapses of patients on mesalazine (38/112 = 33.9 percent), the probiotic group had a similar percentage of relapse (40/110 = 36.4 percent). "The probiotic drug E. coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with UC" and that these results re-emphasize "the pathogenetic significance of the enteric flora."

Although both groups tolerated their treatment well with no reported adverse side effects, a note of caution should be raised about mesalazine, since it has been the subject of research regarding dangerous side effects that include pancreas and kidney damage,5 making probiotics all the more reasonable as an effective option for UC.

1 Botoman VA. Management of inflammatory bowel disease. Am Fam Physician. 1998 Jan 1;57(1):57-68, 71-2

2 Kanauchi, O. Modification of intestinal flora in the treatment of inflammatory bowel disease. Curr Pharm Des. 2003;9(4):333-46

3 Linskins, RK. The bacterial flora in inflammatory bowel disease: current insights in pathogenesis and the influence of antibiotics and probiotics. Scand J Gastroenterol Suppl. 2001(234):29-40

4 Kruis S. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004 Nov; 53(11): 1617-23

5 Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002 Oct; 51(4): 536-9

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Calming Crohn's Disease with Fish Oil and Antioxidants new
      #136195 - 01/07/05 04:55 PM

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Calming Crohn's Disease with Fish Oil and Antioxidants

By Sheila Russell, Ph.D. Abstracted from "Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease" in the American Journal of Clinical Nutrition 2004;80:1137-44.

Crohn's disease is an inflammatory disease that can affect any area within the gut, including the intestines, stomach, esophagus, and the mouth. This disease can manifest itself at any age, from young childhood to advanced age. Crohn's disease occurs in whites at a rate of 2-5 times than that of non-whites3 and tends to run in some families.

The exact cause of this disease is unknown, and persons afflicted with Crohn's must also contend with two very common complications: malnutrition1 and bone loss.2 The development of malnutrition is due to poor absorption in the diseased area. The cause of bone loss is believed to be part of the inflammatory process. Researchers believe that immune cells present within the diseased area become activated. Then some of these activated cells migrate into the circulation where they cause additional sites of inflammation, such as in the bone, causing bone resorption. Therefore, treatments for this disease need to be able to combat the inflammation, not only in the gut, but also in the bones.

Supplementing with fish oil and antioxidants may be one way to prevent inflammatory cells from forming in the gut and to decreasing the overall tendency of circulating defense cells to cause inflammation. Based on a previous report showing that fish oil could inhibits Crohn's disease relapse in some patients with inactive disease,4 researchers wanted to know if fish oil along with antioxidants could work in patients with active Crohn's disease. Therefore, they conducted a study involving 62 adults with Crohn's disease.

Subjects received, either a fish oil supplement (2.7 g EPA and DHA) and an antioxidant supplement (200 mcg selenium, 3 mg manganese, 30 mg vitamin E, 450 mcg vitamin A and 90 mg vitamin C), or a placebo daily for 24 weeks. Blood samples were drawn to evaluate the effectiveness of the dietary supplements. Researchers analyzed the circulating defense cells to measure changes in the amounts and types of chemicals these cells were producing.

Results from the study showed that in subjects who consumed the fish oil and antioxidants, circulating defense cell contained more EPA and DHA. Circulating defense cells were also producing less inflammatory chemicals. These results are promising and demonstrate that alterations in the consumption of the type of fats in the diet can affect the state of the inflammatory cells. Now, whether or not these alterations within the circulating cells would lead to disease remission is unknown at this time. Additional clinical testing is required in persons with Crohn's disease before the benefits of this regiment can be determined.


1 Harries AD, Jones LA, Heatley RV, Rhodes J. Malnutrition in inflammatory bowel disease: an anthropometric study. Hum Nutr Clin Nutr 1982;36:307-13

2 Bjarnason I, Macpherson A, mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997;40:228-33

3 Crawford JM. The gastrointestinal tract. in Robbins Pathologic Basis of Disease, 5th ed. eds. Cotran RS, Kumar V, Ribbing SL. W.B. Saunders Co. Philadelphia 1994, pg 801

4 Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med 1996;334:1557-41

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Biotic Therapy Cuts Inflammation in Ulcerative Colitis new
      #152022 - 02/19/05 05:59 PM

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Biotic Therapy Cuts Inflammation in Ulcerative Colitis

By David Douglas

NEW YORK (Reuters Health) Feb 04 - Synbiotic therapy, involving prebiotic and probiotic agents, reduces chronic inflammation in patients with active ulcerative colitis, Scottish researchers report in the February issue of Gut.

As lead investigator Dr. Elizabeth Furrie told Reuters Health, "Feeding twice daily with the synbiotic therapy for one month induced highly significant reduction in the inflammatory state of the colon that translated to clinical improvement. This therapy has demonstrated no side effects and can be taken in conjunction with conventional treatment."

Dr. Furrie and colleagues at the University of Dundee note that the immune response to normal commensal microorganisms is believed to be associated with such inflammatory processes in ulcerative colitis.

To see whether modulation of gut flora might alter the disease process, the researchers combined the probiotic Bifidobacterium longum and a prebiotic, the enriched inulin mixture Synergy 1 to provide a growth substrate.

In total, 18 patients with active ulcerative colitis were randomized in a double-blind fashion to 4 weeks of synbiotic therapy or to placebo.

Over this period, sigmoidoscopy scores on a 7-point scale fell in the active treatment group from 4.5 to 3.1. In placebo patients, there was an increase from 2.6 to 3.2.

In addition, mRNA levels of human beta defensins 2, 3 and 4 -- which are strongly upregulated in those with the disease -- were significantly reduced. This was also true of the inflammatory cytokines tumor necrosis factor alpha and interleukin 1 alpha.

Biopsies also showed that the synbiotic group had reduced inflammation as well as regeneration of epithelial tissue.

Following these encouraging results, the researchers call for a large-scale trial to "investigate the long term effect of synbiotic use in inducing and maintaining remission in patients with active disease."

Gut 2005;54:242-249.

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Fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis new
      #173164 - 04/24/05 03:33 PM

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Clinical Gastroenterology and Hepatology
April 2005 • Volume 3 • Number 4

Original Articles

An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: A randomized, controlled trial

Douglas L. Seidner ⁎ ⁎ [MEDLINE LOOKUP]
Bret A. Lashner ⁎ [MEDLINE LOOKUP]
Aaron Brzezinski ⁎ [MEDLINE LOOKUP]
Phillip L.C. Banks ‡ [MEDLINE LOOKUP]
John Goldblum § [MEDLINE LOOKUP]
Claudio Fiocchi ¶ [MEDLINE LOOKUP]
Jeffry Katz ¶ [MEDLINE LOOKUP]
Gary R. Lichtenstein ∥ [MEDLINE LOOKUP]
Peter A. Anton # [MEDLINE LOOKUP]
Keith A. Garleb ‡‡ 1 [MEDLINE LOOKUP]
Stephen J. Demichele ‡‡ 1 [MEDLINE LOOKUP]

The Enteral Nutrition in Ulcerative Colitis Study Group

Background & Aims: N-3 fatty acids from fish oil, antioxidants, and short-chain fatty acids (SCFAs) produced during the fermentation of soluble fiber may attenuate inflammation associated with ulcerative colitis (UC). We assessed the efficacy of a nutritionally balanced oral supplement enriched with fish oil, fructooligosaccharides, gum arabic, vitamin E, vitamin C, and selenium on disease activity and medication use in adults with mild to moderate UC.

Methods: A total of 121 patients with UC and a disease activity index (DAI) from 3–9 on a 12-point scale were block randomized for extent of disease and smoking status. In addition to their usual diet, patients consumed 18 oz of the oral supplement or a carbohydrate-based placebo formula each day for 6 months. Clinical and histologic responses were assessed at 3 and 6 months or at the final visit. A change in average prednisone use between groups was tested by using a linear mixed-effects model. Results: Eighty-six patients completed the study. Baseline characteristics were not different between groups except for a higher total DAI score in the oral supplement group (7.3 ± 1.3; n = 36) compared with the placebo group (6.2 ± 2.0; n = 50) (P < .05). Both groups showed significant and similar degree of improvement at 6 months in DAI (&#8722;2.5 for oral supplement and &#8722;2.8 for placebo) and histologic index (&#8722;1.9 for oral supplement vs. &#8722;2.0 for placebo). Both intent-to-treat and completed patients given oral supplement had a significantly greater rate of decrease in the dose of prednisone required to control clinical symptoms over 6 months as compared with the placebo group (P < .001).

Conclusions: The improvement in clinical response combined with a decreased requirement for corticosteroids suggest that this enriched oral supplement can be a useful adjuvant therapy in patients with UC.

Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
§Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
‡STATPROBE, Dublin, Ohio, USA
¶Department of Gastroenterology, Case Western Reserve University, Cleveland, Ohio, USA
&#8741;Department of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
#Department of Gastroenterology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
&#8270;&#8270;Department of Gastroenterology, University of Southern California Medical Center, Los Angeles, California
‡‡Strategic Discovery R&D, Ross Products Division, Abbott Laboratories, Columbus, Ohio, USA
Supported in part by a grant from Ross Products Division, Abbott Laboratories.
1Drs Garleb and Demichele are employees of Ross Products Division, Abbott Laboratories.
&#8270;Address requests for reprints to: Douglas L. Seidner, MD, Department of Gastroenterology\A30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195fax: (216) 444-6305.
Email address: (Douglas L. Seidner)
Copyright © 2005 by American Gastroenterological Association

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IBD Patients May Benefit From Folic Acid Supplementation new
      #180700 - 05/22/05 07:02 PM

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IBD Patients May Benefit From Folic Acid Supplementation

NEW YORK (Reuters Health) Apr 29 - Homocysteine levels are increased in both the mucosa and blood of patients with Crohn's disease and ulcerative colitis, according to a new study, suggesting that this molecule may play a pathogenic role in intestinal inflammation. Further, the effect could be abolished by folate supplementation.

Elevated homocysteine "contributes to the pathophysiology" of several chronic inflammatory diseases, investigators note in the April issue of the American Journal of Gastroenterology. But whether homocysteine is involved in mucosal inflammation in patients with inflammatory bowel disease (IBD) has not been explored, until now.

In their study of 83 patients with Crohn's, 83 with ulcerative colitis, and 70 healthy controls, plasma and mucosal homocysteine levels were significantly higher in IBD patients relative to control subjects.

Specifically, they observed that IBD-derived intestinal lamina propria mononuclear cells (LPMC) released higher homocysteine than control-derived LPMC.

Culturing intestinal microvascular endothelial cells in homocysteine alone, or in combination with TNF-alpha to mimic the in vivo IBD intestinal conditions, effectively triggered an inflammatory reaction in these cells, leading to upregulation of various endothelial cell adhesion molecules.

The team also observed low folate levels in the IBD patients. Folate levels were inversely correlated with homocysteine levels and, in in vitro studies, the addition of folic acid, a homocysteine scavenger, blocked the homocysteine-triggered inflammatory effects.

Therefore, Dr. Silvio Danese, from Catholic University in Rome, Italy and colleagues think it would be "reasonable to hypothesize a beneficial effect of folic acid supplementation in IBD patents to eliminate the homocysteine-mediated inflammatory events, especially mononuclear cell adhesion."

Am J Gastroenterol 2005;100:896-895.:

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The Clinical Epidemiology of Inflammatory Bowel Disease
      #207552 - 08/22/05 04:45 PM

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The Clinical Epidemiology of Inflammatory Bowel Disease

Bret A. Lashner, MD

Several important advances regarding the clinical epidemiology of inflammatory bowel disease (IBD) were presented during this year's Digestive Disease Week (DDW) meeting. Among the advanced imaging techniques examined, computed tomography (CT) enterography, chromoendoscopy, and magnetic resonance (MR) colography appear to be the leading technologies, whereas wireless capsule endoscopy appears to be less useful than previously believed. Additionally, genetic linkages in IBD are being discovered or confirmed at a very rapid rate, as highlighted in key discussions during these meeting proceedings. Investigators are also elucidating the natural history of IBD from large, meticulously maintained databases to confirm incidence and surgery rates, associations with other diseases, and risk of complications, such as pouchitis or cancer. As further evident from the focus of key sessions at this year's meeting, cancer surveillance in IBD remains a hotly debated topic with somewhat conflicting studies to sort through.

This clinical overview discusses some of the more key DDW sessions documenting these advances.

Advanced Imaging in IBD
There is mounting evidence that chromoendoscopy is a preferred imaging technique for cancer surveillance in ulcerative colitis. This technique could be improved even further with the addition of confocal laser microscopy. In a randomized clinical trial involving 153 patients with long-standing ulcerative colitis, 80 patients underwent conventional colonoscopic surveillance and 73 underwent chromoendoscopy with confocal endomicroscopy for detection of lesions suspicious for neoplasia.[1] Significantly more neoplastic lesions were found in the chromoendoscopy group (19 vs 4; P = .0007). Compared with conventional histology, confocal endomicroscopy had a sensitivity of 95% and a specificity of 98% for identifying neoplastic lesions Therefore, the study authors concluded that chromoendoscopy, as compared with conventional endoscopy, was able to identify lesions likely to be neoplastic, and that confocal laser microscopy could confirm neoplasia in these lesions in vivo.

Wireless capsule endoscopy is used in clinical practice to diagnose Crohn's disease or as a tool to assess extent and severity of disease. In a study by Esrailian and colleagues[2] presented during these meeting proceedings, 41 experts in IBD were asked to judge the appropriateness of wireless capsule endoscopy in 5 case scenarios. The overwhelming majority of experts (> 83% for each case) deemed wireless capsule technology to be "inappropriate" in cases of (1) suspected Crohn's disease; (2) newly diagnosed Crohn's disease; (3) new perianal fistulas; (4) steroid-refractory stricture in Crohn's disease; and (5) postoperative fibrostenotic Crohn's disease. At the present time, experts seem to agree that wireless capsule endoscopy is not helpful in the diagnosis or management of patients with Crohn's disease. Children may be at higher risk than adults for complications from wireless capsule endoscopy. Indeed, a retrospective review by Moy and colleagues[3] found a 22.5% risk for complications among 32 studies in 31 children. Three patients had capsules that did not pass the pylorus by 8 hours (2 patients needed endoscopic removal) and 4 had capsules that did not pass through the small bowel (3 required surgical removal or bowel resection and 1 required steroid treatment). Thus, it is doubtful that the potential benefits of wireless capsule endoscopy justify the risk in pediatric patients.

The utility of CT enterography was evaluated in 51 patients with Crohn's disease of the small bowel to determine whether the additional information provided by this modality changed clinical management (eg, steroid use choices).[4] Although CT enterography correlated poorly with other radiologic and clinical findings, it did change management in 34 (67%) of the patients. On the basis of the additional findings on CT enterography, steroids were added in the management of 14 patients, and 20 patients had steroid therapy reduced or eliminated. Therefore, such application of technology appears to be promising.

Solem and colleagues[5] compared the sensitivity, specificity, and accuracy of CT enterography, wireless capsule endoscopy, small bowel x-ray, and ileoscopy during colonoscopy in the diagnosis of small bowel Crohn's disease. Forty-two patients with suspected or known Crohn's disease were offered all 4 tests sequentially. CT enterography and ileocolonoscopy had the highest accuracy (86% and 85%, respectively). Small bowel x-ray had an accuracy of 79% due to a relatively low sensitivity (65%), and wireless capsule endoscopy had a low accuracy (67%) due to a poor specificity (53%). On the basis of these results, CT enterography appears likely to improve our current approach to diagnosing Crohn's disease.

MR colonography, without colonic cleansing, has been proposed for use in the pediatric IBD patient. In a study by Falconieri and colleagues,[6] 22 pediatric patients (14 with ulcerative colitis, 2 with Crohn's disease, and 6 normal [controls]) underwent unprepped MR colonography to compare the findings with colonoscopy. Twelve of the 14 patients with ulcerative colitis had thickened bowel wall (abnormal MR colonography) that correlated with the extent of disease. The sensitivity and specificity of this test was 81% and 85%, respectively. Thus, on the basis of these findings, MR colonography, with no radiation exposure and no preparation, has certain advantages over other forms of testing for investigation of colonic involvement in pediatric IBD.

Genetic Susceptibility in IBD
Some patients with chronic pouchitis may have undiagnosed Crohn's disease. Pouchitis is a common complication after ileal pouch-anal anastomosis for ulcerative colitis, and innate immune responses targeted against enteric bacteria have a role in its pathogenesis. Meier and colleagues[7] conducted a retrospective study of 97 patients with ileal pouch-anal anastomoses to determine whether genetic polymorphisms in the innate immune receptor toll-like receptor 4 and the IBD susceptibility gene NOD2/CARD15 were associated with pouchitis. The L1007fsinsC mutation in CARD15 was found to be associated with chronic pouchitis -- all patients who harbored this mutation developed pouchitis. No patient with intermittent pouchitis or no pouchitis was found to harbor this mutation. Additionally, the toll-like receptor 4 polymorphisms, a common defect in innate immunity dysfunction, were not associated with pouchitis. The study authors concluded that patients with chronic pouchitis had genetic polymorphisms similar to those found in patients with Crohn's disease, whereas in those without pouchitis, the frequency of these polymorphisms was similar to that reported in ulcerative colitis patients and the general population. Thus, CARD15 mutations, particularly the L1007fsinsC polymorphism, may predispose to the development of chronic pouchitis following ileal pouch-anal anastomosis for ulcerative colitis.

There is a purported linkage with IBD on chromosome 10 near the DLG5 gene (codes for an important scaffolding protein). Cummings and colleagues[8] conducted a case-control study to examine the contribution of variants in this gene to disease heterogeneity in IBD. The study authors compared 699 IBD patients with 360 controls; no associations with DLG5 polymorphisms were found, even when patients were stratified according to CARD15 polymorphisms. In another cohort involving 981 IBD patients and 305 controls, the OCTN (carnitine/organic cation transporter) gene cluster on chromosome 5 (the IBD5 locus) was found to be associated with fistulizing Crohn's disease (odds ratio [OR]: 1.47, 95% confidence interval [CI] 1.03-2.11).[9] No associations with IBD (ie, a particular phenotype) were found for the DLG5 gene.

Studying phenotypic homogeneous subgroups of IBD patients may increase the likelihood of finding genotype-phenotype correlations. In a study involving 867 IBD-affected relative pairs, linkage was found for CARD15 (IBD1 locus) and ileal Crohn's disease (lod score [measure of degree of linkage] = 2.56; P = .035), the IBD2 locus and extensive ulcerative colitis (lod = 3.27; P < .001), Crohn's disease in non-Jewish patients and IBD3 (lod = 2.93 for colonic disease, lod = 2.97 for perianal disease), and evidence for linkage on IBD5 was seen in non-Jewish patients with colonic disease (lod =2.85).[10] Very few of these associations could have been identified without examining homogeneous subgroups.

Blood samples were collected from 595 patients with IBD and 627 controls followed for more than 10 years in the European Cooperative IBD study. Data from this cohort are unique in that they can facilitate the investigation of whether genetic or immune markers influence longitudinal changes in disease phenotypes. Riis and colleagues[11] studied mutations in CARD15 and ASCA (anti-Saccharomyces cerevisiae) with regard to longitudinal changes in disease phenotype among IBD patients The immune marker ASCA and CARD15 were found to be associated with a change in behavior over time from inflammatory to stricturing or fistulizing Crohn's disease (OR: 3.2; 95% CI: 1.2-8.8). Indeed, both genetic factors and abnormal immune responses to bacterial stimuli are believed to play a role in the pathogenesis underlying Crohn's disease. Recently, an association between Crohn's disease and CARD8 located in the IBD6 region (19p13) has been reported. In a study of 354 patients with Crohn's disease and 225 matched controls, the combination of CARD8 mutations in the IBD6 region on chromosome 19 and anti-OmpC (antibody to a protein expressed by Escherichia coli) was found to be synergistically associated with fistulizing Crohn's disease.[12] The study authors theorized that a mutation in the CARD8 protein could lead to a dysregulated immune response that when coupled with an aberrant immune response to commensal bacteria (anti-OmpC mutation) could lead to an aggressive, transmural inflammatory disease.

Natural History of IBD
Autoimmune manifestations are reported to be associated with both Crohn's disease and ulcerative colitis. In this context, Bernstein and colleagues[13] assessed the coincident occurrence of IBD and other autoimmune disorders using population-based data from Manitoba. Odds ratios significantly greater than 1 were found for asthma, bronchitis, and psoriasis with Crohn's disease, and for asthma, bronchitis, psoriasis, multiple sclerosis, and chronic renal disease with ulcerative colitis. Asthma was the most common autoimmune disorder found to be coincident with IBD. Thyroiditis and neuropathy were not more common in patients with IBD compared with controls. In a related investigation, Tang and colleagues[14] conducted a retrospective study using the University of Manitoba IBD database to examine fistula formation in patients with Crohn's disease. They found that 19.2% of the Crohn's disease population had fistulas. If perianal fistulas were present, the risk of having a concomitant luminal fistula was found to be significantly increased (OR: 4.45; 95% CI: 2.92-6.76). Therefore, the presence of perianal fistulas should prompt an examination for luminal fistulous disease. In another study reported during these meeting proceedings, Bernstein and colleagues[15] assessed the burden of IBD using population-based data from 5 provinces in Canada. Incidence rates for Crohn's disease per 100,000 ranged between 12.2 and 22.5, and for ulcerative colitis ranged between 8.6 and 21.2. Prevalence of disease per 100,000 persons ranged between 231 and 325 for Crohn's disease, and between 182 and 255 for ulcerative colitis. For all IBD, the female:male ratio ranged from 1.14 to 1.29. Thus, overall, the prevalence of IBD in Canada was found to be 491/100,000 persons; that is, 0.5% of the population has IBD.

Is there an association between early postoperative pouch histology and development of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis? To predict the development of acute or chronic pouchitis, investigators from Toronto took biopsies from the pouch of patients soon after surgery and evaluated 109 patients for a mean of 11.5 years.[16] Early inflammation was found to be a predictor of chronic pouchitis (hazard ratio 7.4; 95% CI: 2.14-24.2). The investigators suggested that such patients should be considered for early prophylactic therapy to prevent development of chronic pouchitis. Early histology did not predict the occurrence of acute pouchitis.

What is the colectomy risk in ulcerative colitis after 10 years? The European Cohort IBD group studied 784 patients with ulcerative colitis for a minimum of 10 years to evaluate colectomy rates.[17] They found that only 7.6% of patients had colectomies. It is interesting to note that northern European countries had much higher colectomy rates than southern European countries. Despite the fact that no information on extent of disease was presented, the purported colectomy rate of 20% to 30% in patients with ulcerative colitis is likely to be a gross overestimate.

Cancer Surveillance in IBD
Are older patients with late-onset IBD at risk for colorectal cancer and do they require frequent colonoscopic surveillance? Investigators from the Hines VA Hospital in Hines, Illinois, followed 114 older ulcerative colitis patients with late-onset disease and compared outcomes with a comparable group of 6829 non-IBD controls.[18] The annual incidence of cancer in the ulcerative colitis group was 0.14% compared with 0.11% in controls (P = not significant). On the basis of these findings, the investigators suggested that older patients with late-onset ulcerative colitis should undergo surveillance at the same intervals suggested for those with sporadic disease.

The long-term safety of infliximab, an anti-tumor necrosis factor-alpha monoclonal antibody, is currently under investigation. In a case-control study, Biancone and colleagues[19] evaluated the development of neoplasia in 392 patients with Crohn's disease treated with infliximab compared with matched controls. Nine patients treated with infliximab and 6 controls developed neoplasia (OR: 1.51; P = .60). Among those patients in the infliximab-treated group who developed neoplasia, there was 1 cholangiocarcinoma, 3 breast cancers, 2 skin cancers, 1 laryngeal cancer, and 2 anal canal cancers. Among the controls who developed neoplasia, there was 1 ileal adenocarcinoma, 2 skin cancers, 1 lymphoma, 1 cecal adenocarcinoma, and 1 breast cancer. Thus, the results of this study suggest that infliximab did not significantly increase the risk of neoplasia.

Recent reports have suggested that dysplasia and colorectal cancer may be endoscopically visible in many patients with IBD. Rubin and colleagues[20] conducted a retrospective review of a large registry of patients with ulcerative colitis who underwent surveillance examinations over a 10-year period; 1339 examinations were performed in 622 patients. Sixty-four dysplastic lesions were found in 44 patients during this study interval; 35 of 56 (62.5%) dysplastic lesions were visible to the endoscopist, and 7 of 8 (87.5%) cancers were visible. Visible lesions included polyps or masses, strictures, or irregular mucosa. The sensitivity of visibly (ie, by endoscopy) identifying neoplastic lesions was 79.5%. Chromoendoscopy is likely to increase this sensitivity rate much further by making even more lesions visible.

At present, it remains unclear why some patients with IBD have an increased risk of colorectal neoplasia. Jess and colleagues[21] conducted a nested case-control study to investigate risk factors for colorectal neoplasia in 2 large population-based IBD cohorts; 52 patients with ulcerative colitis and neoplasia were compared with a matched set of controls. Significant risk factors for neoplasia included primary sclerosing cholangitis (OR: 8.7), active disease (OR: 3.1), continuously active disease for more than 1 year (OR: 4.0), sulfasalazine use (OR: 1.13), mesalamine use (OR: 1.22), and a higher cumulative dose of steroids (OR: 1.05). These study findings did not support the accumulating evidence that mesalamine may have chemopreventive effects for neoplasia.

Results of population-based studies have demonstrated a slightly increased mortality rate for patients with Crohn's disease over the last 40 years. Wolters and colleagues[22] presented the results of a study assessing mortality risk in a European cohort of Crohn's disease patients 10 years post diagnosis. In this European cooperative study of 371 incident cases of Crohn's disease followed for at least a decade, there were 37 deaths (SMR [standardized mortality ratio] 1.72; 95% CI: 1.21-2.38). There were 8 deaths from gastrointestinal malignancies vs only 0.86 expected (SMR 8.14; 95% CI: 3.26-16.78). In this cohort, patients with Crohn's disease had an increased mortality risk, especially from gastrointestinal malignancies.

Recent reports have suggested a high risk for progression to high-grade dysplasia or cancer among IBD patients with flat low-grade dysplasia; this has led to more aggressive surgical intervention. Jess and colleagues[23] reported the results of a study to assess the true long-term outcome of colorectal dysplasia in a population-based IBD cohort. Among 691 incident ulcerative colitis cases followed in a cancer surveillance program, there were 9 with dysplasia in flat mucosa, 1 with a dysplasia-associated lesion or mass (DALM), and 23 with adenoma-like masses (ALMs). In patients with ALMs, 3 had recurrent adenomas, 3 developed flat low-grade dysplasia, 2 developed DALMs, and 1 developed multifocal Dukes' C adenocarcinoma. Although these findings did not confirm the previously reported risk for progression in flat dysplastic lesions, they did document ALMs as worrisome lesions in patients with ulcerative colitis.

On the basis of data presented during this year's DDW meeting, and as discussed above, the clinical care of IBD patients may evolve and change. Although findings suggest that CT enterography and MR colography will be used more often to diagnose IBD and its complications; wireless capsule endoscopy has not yet found its place in the care of these patients. Chromoendoscopy is sure to improve outcomes from cancer in IBD, but much additional study is needed regarding treatment recommendations for lesions found with such testing. Last, as investigators continue to identify and confirm genes associated with IBD, the closer clinicians are to finding the cause and cure of IBD.

Kiesslich R, Goetz M, Schneider C, et al. Confocal endomicroscopy as a novel method to diagnose colitis-associated neoplasm in ulcerative colitis: A prospective randomized trial. Gastroenterology. 2005;128(suppl 2):A-73. [Abstract 483]
Esrailian E, Targownik EL, Spiegel BM, et al. Is wireless capsule endoscopy appropriate for the diagnosis and management of Crohn's disease? A survey of North American Inflammatory Bowel Disease experts. Gastroenterology. 2005;128(suppl 2):A-73. [Abstract 484]
Moy L, Levine J. Wireless capsule endoscopy in the pediatric age group: Experience and complications. Gastroenterology. 2005;128(suppl 2):A-73. [Abstract 485]
Higgins PD, Caoili E, Zimmermann M, et al. CT enterography adds information to clinical management in small bowel Crohn's disease. Gastroenterology. 2005;128(suppl 2):A73-A74. [Abstract 487]
Solem CA, Loftus EV, Fletcher JG, et al. Small bowel imaging in Crohn's disease: A prospective, blinded, 4-way comparison trial. Gastroenterology. 2005;128(suppl 2):A74 [Abstract 488]
Falconieri P, Laghi A, Paolantonio P, et al. Un-prepped MR colonography in pediatric patients with inflammatory bowel disease. Gastroenterology. 2005;128(suppl 2):A-49. [Abstract 342]
Meier C, Aisenberg J, Legnant P, et al. Innate immune receptor polymorphisms in pouchitis: Is NOD2/CARD15 a susceptibility factor? Gastroenterology. 2005;128(suppl 2):A-112. [Abstract 726]
Cummings JRF, Kerrlinger KR, Ahmad T, Jewell DP. Genotype-phenotype analyses of the IBD susceptibility gene DLG5. Gastroenterology. 2005;128(suppl 2):A-112. [Abstract 727]
Vermeire S, Pierik M. Henckaerts L, et al. Study on DLG5 and OCTN polymorphisms shows association of the OCTN TC risk haplotype with perianal and fistulizing Crohn's disease but not with susceptibility to IBD. Gastroenterology. 2005;128(suppl 2):A-113. [Abstract 731]
Achkar JP, Dassopoulous T, Silverberg M, et al. Disease location refines genomic localization in inflammatory bowel disease: IBD is an extensive ulcerative colitis locus. Gastroenterology. 2005;128(suppl 2):A-112-A113. [Abstract 728]
Riis L, Wolters F, Solberg C, et al. ASCA is associated with CARD15 mutations and longitudinal changes in behavior of Crohn's disease: A population based ED-IBD study. Gastroenterology. 2005;128(suppl 2):A-113. [Abstract 729]
Picornell Y, Abreu MT, Ippoliti A, et al. CARD8 variant and the expression of anti-OmpC are synergistically associated with internal penetrating Crohn's disease. Gastroenterology. 2005;128(suppl 2):A-113.[Abstract 730]
Bernstein CN, Blanchard JF, Wajda A. A population-based study of comorbidity and other autoimmune diseases in IBD. Gastroenterology. 2005;128(suppl 2):A-113. [Abstract 732]
Tang LY, Rawsthorne P, Bernstein CN. In Crohn's disease is there an association between perianal fistulzing disease and luminal fistulizing disease? A population-based study. Gastroenterology. 2005;128(suppl 2):A-113-A114. [Abstract 733]
Bernstein CN, Wajda A, Blanchard JF, et al. The burden of IBD in Canada: A population-based study. Gastroenterology. 2005;128(suppl 2):A-114. [Abstract 735]
Johnson P, MacNeill N, Baladjay L, et al. Early post-operative pouch histology predicts future chronic pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. Gastroenterology. 2005;128(suppl 2):A-114. [Abstract 734]
Hoie C, Wolters F, Riis L, et al. Colectomy rates in ulcerative colitis in a European inception cohort followed for ten years by the EC-IBD study group. Gastroenterology. 2005;128(suppl 2):A-114. [Abstract 736]
Hoffman SD, Sontag SJ, Levis W, et al. Late onset inflammatory bowel disease in older patients does not require frequent surveillance. Gastroenterology. 2005;128(suppl 2):A-121-A122. [Abstract 777]
Biancone L, Kohn A, Colombo E, et al. Development of neoplasia in Crohn's disease patients treated with infliximab: A case-control study in an Italian population. Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 778]
Rubin DT, Rothe JA, Cohen RD, Hanauer SB. Is dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 779]
Jess T, Loftus EV, Velayos FS, et al. Risk factors for cancer and dysplasia in inflammatory bowel disease: A nested case-control study of population-based cohorts from Copenhagen County and Olmsted County. Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 780]
Wolters F, Schouten L, Sijbrandij J, et al. Increased mortality ten years after diagnosis in a Europe-wide population based cohort of Crohn's disease patients (EC-IBD Study Group). Gastroenterology. 2005;128(suppl 2):A-122. [Abstract 781]
Jess T, Loftus EV, Velayos FS, et al. Are adenomas more harmful than flat low-grade dysplasia in patients with inflammatory bowel disease? A population-based cohort study from Olmsted County, Minnesota, 1940-2002. Gastroenterology. 2005;128(suppl 2):A-123. [Abstract 782]

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Differentiation of Inflammatory Bowel Disease and Irritable Bowel Syndrome new
      #210440 - 09/01/05 11:13 AM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Rectal Mucosal Nitric Oxide in Differentiation of Inflammatory Bowel Disease and Irritable Bowel Syndrome

Clinical Gastroenterology and Hepatology
Volume 3, Issue 8 , August 2005, Pages 777-783

Claudia I. Reinders, Max Herulf;, Tryggve Ljung, Jakob Hollenberg, Eddie Weitzberg§, Jon O. Lundberg, and Per M. Hellström

Division of Pharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
‡Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna, Stockholm, Sweden
§Department of Anaesthesiology and Intensive Care, Karolinska University Hospital Solna, Stockholm, Sweden

Background & Aims: Differentiating patients with functional bowel disorders from those with inflammatory bowel disease (IBD) can be difficult. Rectal luminal levels of nitric oxide (NO) are greatly increased in IBD. To further evaluate this disease marker, we compared NO in patients with irritable bowel syndrome (IBS) with those found in patients with active IBD and in healthy control subjects. Methods: Rectal NO was measured with chemiluminescence technique by using a tonometric balloon method in 28 healthy volunteers, 39 patients with IBS, 86 with IBD (Crohn's disease and ulcerative colitis), and 12 patients with collagenous colitis. In addition, NO was measured before and after a 4-week treatment period in patients with active ulcerative colitis and repeatedly during 2 weeks in healthy volunteers. Results: NO was low in healthy control subjects (median, 45; 25th–75th percentile, 34–64 parts per billion [ppb]), and variations over time were small. In IBS patients NO was slightly increased (150, 53–200 ppb; P < .001), whereas patients with active IBD or collagenous colitis had greatly increased NO levels (3475, 575–8850 ppb, and 9950, 4475–19,750 ppb, respectively; P < .001). With a cutoff level of 250 ppb, NO had a sensitivity of 95% and a specificity of 91% in discriminating between active bowel inflammation and IBS. Rectal NO correlated with disease activity in IBD and collagenous colitis and decreased markedly in IBD patients responding to anti-inflammatory treatment. Conclusions: Rectal NO is a minimally invasive and rapid tool for discriminating between active bowel inflammation and IBS and a possibly useful add-on for monitoring patients with IBD.

Abbreviations used in this paper: CI, confidence interval; GI, gastrointestinal; HBI, Harvey Bradshaw index; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; NO, nitric oxide; ppb, parts per billion

Supported by grants from the Knowledge Foundation, the Swedish Research Council, and Karolinska Institutet. Eddie Weitzberg and Jon O. Lundberg own shares in Aerocrine AB, a company that manufactures equipment for measurements of nitric oxide.
Address requests for reprints to: Claudia Reinders, MSc, Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. fax: +46 8 33 22 78.!&_cdi=20161&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f0dd70723cf0e5dc95f617a69215484f

Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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Cannabinoids Show Promise for Inflammatory Bowel Disease new
      #210445 - 09/01/05 11:23 AM

Reged: 12/09/02
Posts: 7798
Loc: Seattle, WA

Cannabinoids Show Promise for Inflammatory Bowel Disease

NEW YORK (Reuters Health) Aug 12 - Cannabis-based drugs may have therapeutic potential in inflammatory bowel disease, UK researchers report in the August issue of Gastroenterology.

"The system that responds to cannabis in the brain is present and functioning in the lining of the gut," lead researcher Dr. Karen Wright, of the University of Bath, explained to Reuters Health. "There is an increased presence of one component of this system during inflammatory bowel diseases -- Crohn's and ulcerative colitis."

Dr. Wright and her colleagues established the location of cannabinoid receptors CB1 and CB2 in human colonic tissue and used human colonic epithelial cells lines in cannabinoid-binding and in wound-healing experiments.

Expression of both receptors was detected on plasma cells in the lamina propria, but only CB2 was present on macrophages.

CB2 was increased and immunoreactivity was seen in the epithelium of colonic tissue characteristic of inflammatory bowel disease. Cannabinoids enhanced epithelial wound closure via CB1-related mechanisms.

Thus continued Dr. Wright, "cannabinoids, which we make ourselves, as well as synthetic cannabinoids, can promote wound healing in the gut, which is extremely interesting given that inflammatory bowel disease involves damaged gut linings."

Although no data are available yet, she added, relevant case studies of the use of cannabinoids are taking place in the UK and a clinical trial is being conducted in Germany.

Gastroenterology 2005.

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