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Risk factors for clinical phenotypes of Crohn's disease of the ileal pouch.

BACKGROUND: Crohn's disease (CD) of the pouch can occur in patients with colectomy and ileal pouch-anal anastomosis (IPAA) originally performed for a preoperative diagnosis of ulcerative colitis. The clinical presentations of CD of the pouch are inflammatory, fibrostenotic, and fistulizing. Risk factors for clinical phenotypes of CD of the pouch have not been characterized. METHODS: A total of 78 eligible patients with CD of the pouch together with 294 nonselected non-CD patients with IPAA seen in the Pouchitis Clinic were enrolled, including 28 with inflammatory CD, 18 with fibrostenotic CD, and 32 with fistulizing CD. The clinical phenotypes of CD were diagnosed based on a combined assessment of clinical, endoscopic, radiographic, and histologic features. Three separate analyses were performed, and for each analysis, the outcome of interest was having one of the phenotypes versus not having it. A stepwise selection multivariable logistic regression analysis was used. RESULTS: In the multivariable analysis, the risk factor for inflammatory CD was higher afferent-limb endoscopy scores (hazard ratio [HR] 1.87 95% confidence interval [CI] 1.54-2.27); the risk factors for fibrostenotic CD were higher afferent-limb (95% CI 1.81-3.48, HR 2.51) and higher cuff (95% CI 1.01-1.84, HR 1.36) endoscopy scores; and for fistulizing CD the risk factors were younger age (95% CI 0.93-0.99, HR 0.96), female gender (95% CI 1.35-6.97, HR 3.07), a preoperative diagnosis of indeterminate colitis (95% CI 1.72-9.34, HR 4.00), and no use of nonsteroidal antiinflammatory drugs (95% CI 1.31-8.25, HR 3.28). CONCLUSIONS: Each of the three phenotypes of CD of the pouch was associated with certain risk factors, suggesting that each of these diseases has a different etiology and disease process. The identification and management of some of the modifiable risk factors may reduce CD-related morbidity.

Adult↗

Microbiologic assessment of tissue biopsy samples from ileal pouch patients.

Tissue biopsy samples from patients with and without ileal pouches were examined by electron microscopic and microbiologic culture techniques to determine the numbers and types of microorganisms closely associated with or within the tissue biopsy samples. The disease status of each patient was determined by endoscopic and histopathologic methods. Of the 78 biopsy samples included in this study, 64 (82%) yielded obligately anaerobic and/or facultative bacteria when they were cultured. Fourteen of the 78 samples (17.9%) were negative by culture. Of the positive samples, 54 contained facultatively anaerobic bacterial species and 50 yielded obligately anaerobic species. The total counts for facultatively anaerobic bacteria for samples from patients with pouchitis were significantly greater than for samples from patients in control groups. In addition, the number of samples from patients with normal pouches that did not contain obligate anaerobes was significantly less than that from patients with pouchitis; 4 of 23 and 6 of 12 samples, respectively (P less than 0.043). For samples in which organisms were detected, there was agreement with electron microscopic detection of bacteria in 23 of 27 samples, for an overall sensitivity of electron microscopy compared with that of culture of 85%. The qualitative studies resulted in the characterization of 273 isolates comprising 77 different phenotypes. The specificity of these findings in patients with ileal pouchitis is discussed.

Bacteria, Anaerobic↗

Ulcerative colitis.

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Cholangitis, Sclerosing↗

Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis.

BACKGROUND: Increased infertility in women has been reported after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis but reported infertility rates vary substantially. AIMS: (1) To perform a systematic review and meta-analysis of the relative risk of infertility post-IPAA compared with medical management; (2) to estimate the rate of infertility post-IPAA; and (3) to identify modifiable risk factors which contribute to infertility. METHODS: Medline, EMBASE, Current Contents, meeting abstracts, and bibliographies were searched independently by two investigators. The titles and abstracts of 189 potentially relevant studies were reviewed; eight met the criteria and all data were extracted independently. Consensus was achieved on each data point, and fixed effects meta-analyses, a funnel plot, and sensitivity analyses were performed. RESULTS: The initial meta-analysis of eight studies had significant heterogeneity (p = 0.004) due to one study with very high preoperative infertility (38%). When this study was omitted, the relative risk of infertility after IPAA was 3.17 (2.41-4.18), with non-significant heterogeneity. The weighted average infertility rate in medically treated ulcerative colitis was 15% for all seven studies, and the weighted average infertility rate was 48% after IPAA (50% if all eight studies are included). We were unable to identify any procedural factors that consistently affected the risk of infertility. CONCLUSIONS: IPAA increases the risk of infertility in women with ulcerative colitis by approximately threefold. Infertility, defined as achieving pregnancy in 12 months of attempting conception, increased from 15% to 48% in women post-IPAA for ulcerative colitis. This provides a basis for counselling patients considering colectomy with IPAA. Further studies of modifiable risk factors are needed.

Colitis, Ulcerative↗

Distribution of mucosal pathology and an assessment of colonic phenotypic change in the pelvic ileal reservoir.

The mucosa of the pelvic ileal reservoir undergoes adaptive changes--inflammatory, architectural, and metaplastic--on exposure to the faecal stream. Twenty three quadruple loop ileal pouches constructed for ulcerative colitis (20 patients) and familial adenomatous polyposis (FAP) (three patients) were studied. No patient fulfilled clinical, endoscopic, or histopathological criteria for pouchitis. Standard duplicate biopsy specimens were taken from the proximal limb, the anterior wall, the posterior wall, and the body of the reservoir. An established scoring system was used and showed a highly significant increase in inflammatory scores in posterior wall biopsy specimens compared with those from the anterior wall. These results suggest that the adaptive changes are the direct result of contact with static faecal contents. One patient only showed significant inflammation in the proximal limb. There was no evidence of mucosal prolapse in any anterior wall biopsy specimen. Patients with colitis showed substantially more inflammatory and architectural changes than those with FAP. Ninety six per cent of pouches showed some colonic phenotypic expression as defined by mucin histochemical and PR 3A5 immunohistochemical studies. Our results suggest, however, that there may not be complete colonic metaplasia and that the mucin changes and other phenotypic alterations may represent a non-specific response to pouch inflammation and not a prerequisite for the development of pouchitis. The focal nature of the inflammatory and architectural changes, which may be the result of direct contact with static faecal residue, are clearly shown. A single random biopsy specimen of pouch mucosa is of limited value in assessing pathological changes and screening for potential neoplastic change within the reservoir.

Adenomatous Polyposis Coli↗

Refractory pouchitis: does it reflect underlying Crohn's disease?

Typical 'pouchitis' is a well recognised complication of ileal pouches in ulcerative colitis. Infrequently, a refractory pouchitis (RP) presents with certain clinical, endoscopic, and pathological features resembling Crohn's disease and is often ascribed to misdiagnosis of the initial colitis. To test that hypothesis and to identify risk factors for RP, this study reviewed cases of presumed ulcerative colitis with ileal pouches constructed at The Mount Sinai Hospital between 1973 and 1986. Twenty four cases with RP (16 Kock pouches and eight pelvic pouches) and 21 controls were compared for eight clinical variables. The original colectomy slides from 15 RP and 18 control cases were reviewed blindly, classified into five histological categories (corresponding to definite ulcerative colitis, definite Crohn's disease, and three indeterminate groups), and scored for 23 histological features. There were no significant clinical differences between RP and control cases except for more frequent extraintestinal manifestations (38% v 5%) and male preponderance (79% v 43%) in RP. There were also no significant differences between the distributions of RP cases and controls among the five histological categories or in the 23 histological features studied. Refractory pouchitis therefore does not seem to reflect underlying Crohn's disease, but may be linked to immunological mechanisms that are manifested clinically as extraintestinal complications.

Adult↗

Increased leukotriene B4 release from ileal pouch mucosa in ulcerative colitis compared with familial adenomatous polyposis.

Pouchitis may complicate the construction of an ileal pouch after colectomy for ulcerative colitis (UC) but not familial adenomatous polyposis (FAP). To examine whether differences in eicosanoid metabolism might explain why pouchitis is largely confined to UC patients, this study compared arachidonic acid stimulated release of immunoreactive leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) from macroscopically uninflamed pouch mucosal biopsy specimens incubated in vitro from patients with UC and FAP. The study also compared eicosanoid release from inflamed and uninflamed pouches in patients with UC. In uninflamed pouches, median LTB4 release was nearly twice as high in UC as in FAP (p = 0.001), but there was no significant difference in PGE2 production. In UC, stimulated eicosanoid release from uninflamed functioning pouch mucosa was not significantly different from that from either ileostomy or defunctioned pouch mucosa. LTB4 and PGE2 release were significantly greater from inflamed than uninflamed pouch mucosa in UC (p = 0.001 and 0.01, respectively). Leukotriene synthesis inhibition or receptor antagonism, or both merit therapeutic evaluation in pouchitis. Increased release of LTB4 from endoscopically normal pouch mucosa suggests increased 5-lipoxygenase activity in patients with UC and could contribute to their predisposition to pouchitis.

Adenomatous Polyposis Coli↗

Polypoid mucosal prolapse in a pelvic ileal reservoir.

A case of a patient who developed a polypoid area of mucosal prolapse three and a half years after having an ileoanal pouch for ulcerative colitis is presented. This seems to be the first published report. This new manifestation of mucosal prolapse in a pelvic ileal reservoir underlines that the pouch as a neorectum is subject to disorders familiar in the rectum.

Adult↗

Relationship of small bowel motility to ileoanal reservoir function.

Some patients with an ileoanal reservoir have a high defecation frequency, despite a good anatomical result and the absence of pouchitis. This study aimed to determine whether variation in function is related to a difference in small bowel motility proximal to the reservoir and if small bowel motility is propagated into the reservoir. Ambulatory small bowel and reservoir motility was studied for 24 hours in five patients with good function (median bowel frequency 4 per day, range 3-6) and seven subjects with poor function (median bowel frequency 12 per day, range 10-20). Five solid state pressure sensors were positioned in the small bowel and one in the reservoir. During the fasting nocturnal period (2300-0800 h), patients with poor function had a median of 10 (range 5-13) migrating motor complexes (MMC), significantly greater (p = 0.03) than the corresponding median number of 3 (range 2-7) in patients with good function. A total of 120 MMCs were observed in the whole series of 12 patients. Of these only two were propagated from the small bowel into the reservoir. Discrete clustered contractions were not propagated into the reservoir, although prolonged propagated contractions did pass into the reservoir in one patient. Patients with poor function had similar 24 hour stool output and radiological reservoir size to those with good function, but the median maximum tolerated volume on reservoir distension was 290 ml (range 160-450) for patients with poor function compared with 475 ml (range 460-550) for patients with good function (p = 0.005). Small bowel motility proximal to the reservoir bears an important relationship to pouch function and defecation frequency. Propagation of coordinated proximal small intestinal motility into the reservoir is rare.

Adult↗

Pouchitis: result of microbial imbalance?

To elucidate the role of microbiological factors in pouchitis, this study investigated the composition of ileal reservoir microflora, the mucus degrading capacity of bacterial enzymes as well as the pH and the proteolytic activity of pouch effluent. Stool samples were collected from five patients with pouchitis and nine patients without pouchitis. The flora of patients with pouchitis had an increased number of aerobes, a decreased ratio anaerobes to aerobes, less bifidobacteria and anaerobic lactobacilli, more Clostridium perfringens, and several species that were not found in control patients (for example, fungi). Furthermore the pH was significantly higher in patients with pouchitis (median value 6.5) than in control patients (5.4). To find out if the pH might influence the breakdown of intestinal mucus glycoproteins, the activity of glycosidases and proteases, and the degradation of hog gastric mucin by the pouch flora was tested at pH 5.2-7.6. Some glycosidases were inhibited, others were stimulated by a low pH, however, in each sample the proteolytic activity was inhibited for 75% at pH 5.2 compared with pH 6.8 and 7.6. Degradation of hog gastric mucin by the pouch flora was an active process at pH 7.2: within two to four hours of incubation more than half of the mucin was degraded. At pH 5.2 it took twice as long. It is concluded that pouchitis possibly results from instability of the flora in the pouch, which causes homeostasis to disappear (dysbiosis), and the protection of the pouch epithelium by the mucus layer becomes affected by increased activity of bacterial and host derived enzymes.

Adenomatous Polyposis Coli↗

Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC), present in 5% of patients with ulcerative colitis, may be associated with pouchitis after ileal pouch-anal anastomosis. The cumulative frequency of pouchitis in patients with and without PSC who underwent ileal pouch-anal anastomosis for ulcerative colitis was determined. A total of 1097 patients who had an ileal pouch-anal anastomosis for ulcerative colitis, 54 with associated PSC, were studied. Pouchitis was defined by clinical criteria in all patients and by clinical, endoscopic, and histological criteria in 83% of PSC patients and 85% of their matched controls. PSC was defined by clinical, radiological, and pathological findings. One or more episodes of pouchitis occurred in 32% of patients without PSC and 63% of patients with PSC. The cumulative risk of pouchitis at one, two, five, and 10 years after ileal pouch-anal anastomosis was 15.5%, 22.5%, 36%, and 45.5% for the patients without PSC and 22%, 43%, 61%, and 79% for the patients with PSC. In the PSC group, the risk of pouchitis was not related to the severity of liver disease. In conclusion, the strong correlation between PSC and pouchitis suggest a common link in their pathogenesis.

Adolescent↗

Leucocyte typing, cytokine expression, and epithelial turnover in the ileal pouch in patients with ulcerative colitis and familial adenomatous polyposis.

BACKGROUND/AIMS: Conventional histopathology, leucocyte typing, cytokine mRNA expression, and crypt cell turnover were compared in ileal pouch biopsy specimens from patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). METHODS: Biopsy specimens were taken from 17 patients with UC and seven with FAP at a median interval of 19 months (range 2-120) after ileostomy closure. All contained both epithelium and lamina propria. Cryostat sections were stained for lymphocyte subtypes (CD3, CD4, CD8), macrophages (CD68), common leucocyte antigen (CD45), and Ki-67, using a three stage immunoperoxidase reaction. Cytokine mRNA expression for interleukins 2 and 6, tumour necrosis factor alpha, and interferon gamma was studied using an in situ hybridisation technique. RESULTS: Lymphocyte subtype and macrophage populations in epithelium and lamina propria were similar in UC and FAP. The labelling index (Ki-67) was significantly increased in biopsy specimens from patients with UC (UC median = 43.3 (interquartile range (IQR) 38.9-48.2) v FAP 34.9 (29.9-35.2), p < 0.05). There was little or no epithelial mRNA expression for any cytokine in any of the specimens. Lamina propria mRNA expression for interleukin 2 was significantly increased in UC (UC median (IQR) 10.7 (5.4-14.2) cells per unit area v FAP 2.8 (1.5-6.6) p < 0.05) but not for tumour necrosis factor alpha, interleukin 6, and interferon gamma. CONCLUSIONS: While static morphological assessment (leucocyte type, conventional histopathological examination) was similar, tests of cell function (mRNA expression and labelling index) were different in ileal pouches in patients with UC compared with FAP. The study also showed that mRNA expression occurred almost entirely in the lamina propria.

Adenomatous Polyposis Coli↗

Antineutrophil cytoplasmic antibodies in sera from colectomised ulcerative colitis patients and its relation to the presence of pouchitis.

BACKGROUND: Few studies have evaluated the influence of colectomy on antineutrophil cytoplasmic antibody (ANCA) positivity in ulcerative colitis (UC). In small series of patients it has been suggested that ANCA positivity in UC might be predictive for development of pouchitis after colectomy. AIMS: To assess the prevalence of ANCA in UC patients treated by colectomy and a Brooke's ileostomy (UC-BI) or ileal pouch anal anastomosis (UC-IPAA), and the relation between the presence of ANCA, the type of surgery, and the presence of pouchitis. SUBJECTS: 63 UC patients treated by colectomy (32 with UC-BI and 31 with UC-IPAA), 54 UC, and 24 controls. METHODS: Samples were obtained at least two years after colectomy. ANCA were detected by indirect immunofluorescent assay. RESULTS: There were no differences between patients with (36.3%) or without pouchitis (35.0%) and between patients with UC (55%), UC-BI (40.6%), and UC-IPAA (35.4%). However, ANCA prevalence significantly decreases in the whole group of operated patients (38.0%) compared with non-operated UC (p = 0.044). CONCLUSIONS: The prevalence of ANCA in operated patients was significantly lower than in non-operated UC, suggesting that it might be related either to the presence of inflamed or diseased tissue. ANCA persistence is not related to the surgical procedure and it should not be used as a marker for predicting the development of pouchitis.

Adult↗

Intestinal permeability in the ileal pouch.

BACKGROUND: Villous atrophy, mucin changes ('colonic metaplasia'), and chronic inflammation occur to varying degrees in all patients with ileal pouchanal anastomosis whereas acute inflammation (pouchitis) affects a subgroup of patients with prior ulcerative colitis. AIM: To measure epithelial barrier function looking for possible functional adaptation in ileal 'pouch' mucosa. PATIENTS: Patients with an ileal pouch prior to ileostomy closure (n = 12), functioning pouch (n = 14), pouchitis (n = 8), and ulcerative colitis (n = 12) were assessed. METHODS: 51Cr-EDTA was administered into the 'pouch' or rectum and urinary recovery over 24 hours was taken as an indication of permeability (barrier function). Histological analysis of 'pouch' biopsy specimens was undertaken. RESULTS: Mucosal permeability is decreased from median 9.4% (range 5.4% to 39.1%) to 1.4% (range 0.38% to 2.2%) after ileostomy closure (p < 0.002) with levels being negatively correlated with two histological parameters of colonic metaplasia-mucin changes (p = 0.03) and villous atrophy (p = 0.05). Pouchitis was associated with increased permeability 5.9% (1.9% to 19.5%) compared with healthy 'pouch' 1.4% (0.35 to 2.2%) (p < 0.006). CONCLUSION: Despite the presence of chronic inflammation in the mature 'pouch' functional adaptation with reduced permeability occurs in conjunction with colonic metaplasia.

Biopsy↗