Adenocarcinoma in an ano-vaginal fistula in Crohn's disease.

INTRODUCTION: Fistulas are a relatively common occurrence in Crohn's disease (CD), and often present early in the disease process. Additionally, patients suffering from either CD or ulcerative colitis are shown to have an increased risk of colorectal malignancies compared with the general population. PRESENTATION OF CASE: We present a case of adenocarcinoma in an ano-vaginal fistula in a patient with longstanding CD. DISCUSSION: Various pathogenic mechanisms for the development of carcinoma in fistulas have been suggested, but there is no consensus and indeed this risk may be cumulative. In this case report, we also discuss the pathogenesis of mucinous adenocarcinoma in fistulas secondary to CD. CONCLUSION: Better detection of adenocarcinoma in patients presenting with persistent non-resolving fistulas in the presence of CD should be undertaken with regular biopsies following examinations under anaesthetic of the anorectum.

The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder.

BACKGROUND: Intestinal mucosal pathology, characterized by ileo-colonic lymphoid nodular hyperplasia (LNH) and mild acute and chronic inflammation of the colorectum, small bowel and stomach, has been reported in children with autistic spectrum disorder (ASD). AIM: To assess ileo-colonic LNH in ASD and control children and to test the hypothesis that there is an association between ileo-colonic LNH and ASD in children. PATIENTS AND METHODS: One hundred and forty-eight consecutive children with ASD (median age 6 years; range 2-16; 127 male) with gastrointestinal symptoms were investigated by ileo-colonoscopy. Macroscopic and histological features were scored and compared with 30 developmentally normal (non-inflammatory bowel disease, non-coeliac disease) controls (median age 7 years; range 1-11; 25 male) showing mild non-specific colitis in 16 cases (13 male) and normal colonic histology in 14 cases (12 male). Seventy-four ASD children and 23 controls also underwent upper gastrointestinal endoscopy. The influence on ileal LNH of dietary restriction, age at colonoscopy, and co-existent LNH elsewhere in the intestine, was examined. RESULTS: The prevalence of LNH was significantly greater in ASD children compared with controls in the ileum (129/144 (90%) vs. 8/27 (30%), P < 0.0001) and colon (88/148 (59%) vs. 7/30 (23%), P = 0.0003), whether or not controls had co-existent colonic inflammation. The severity of ileal LNH was significantly greater in ASD children compared with controls, with moderate to severe ileal LNH present in 98 of 144 (68%) ASD children versus 4 of 27 (15%) controls (P < 0.0001). Severe ileal LNH was associated with co-existent colonic LNH in ASD children (P = 0.01). The presence and severity of ileal LNH was not influenced by either diet or age at colonoscopy (P = 0.2). Isolated ileal LNH without evidence of pathology elsewhere in the intestine was a rare event, occurring in less than 3% of children overall. On histopathological examination, hyperplastic lymphoid follicles are significantly more prevalent in the ileum of ASD children (84/138; 61%) compared with controls (2/23; 9%, P = 0.0001). CONCLUSION: Ileo-colonic LNH is a characteristic pathological finding in children with ASD and gastrointestinal symptoms, and is associated with mucosal inflammation. Differences in age at colonoscopy and diet do not account for these changes. The data support the hypothesis that LNH is a significant pathological finding in ASD children.

Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10.

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.

Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis.

BACKGROUND: Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. METHODS: Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. RESULTS: Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepithelial lymphocytes in surface, foveolar and glandular epithelium. Proliferation of foveolar epithelium was similarly increased in autism, Crohn's disease and H. pylori compared to controls. A striking finding, seen only in 20/25 autistic children, was colocalized deposition of IgG and C1q on the subepithelial basement membrane and the surface epithelium. CONCLUSIONS: These findings demonstrate a focal CD8-dominated gastritis in autistic children, with novel features. The lesion is distinct from the recently recognized focal gastritis of Crohn's disease, which is not CD8-dominated. As in the small intestine, there is epithelial deposition of IgG.

Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology.

Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features; however, links with cognitive function remain unclear. To characterize further, the nature and extent of this disease we examined the mucosal infiltrate using flow cytometry. Duodenal, ileal, and colonic biopsies were obtained from 52 affected children, 25 histologically normal, and 54 histologically inflamed, developmentally normal controls. Epithelial and lamina propria lymphocyte populations were isolated and examined by multicolor flow cytometry. Adjacent biopsies were assessed by semiquantitative histopathology. At all sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in affected children compared with developmentally normal noninflamed control groups (p<0.01) reaching levels similar to inflamed controls. In addition, two populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly increased in affected children compared with both noninflamed and inflamed control groups including IBD, at all sites examined (p<0.01). Histologically there was a prominent mucosal eosinophil infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet, although lymphocyte populations were not influenced by diet. The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.

COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice.

BACKGROUND & AIMS: The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is controversial, but it is thought that cyclooxygenase-1 (COX-1) inhibition is of pivotal importance. We compared small intestinal function and morphology in untreated wild-type, COX-1- and COX-2-deficient mice and the effect of indomethacin, selective COX-1 (SC-560), and COX-2 (celecoxib) inhibition. METHODS: Intestinal permeability ((51)CrEDTA), inflammation (fecal granulocyte marker protein), prostaglandin E(2) (PGE(2)) levels, and macroscopic and microscopic appearances were assessed at baseline and after the drugs. RESULTS: COX-1(-/-) animals were normal except for a 97% decrease in intestinal PGE(2) levels. COX-1(+/+) and COX-1(-/-) animals reacted in a similar way to indomethacin. However, celecoxib, having caused no damage in COX-1(+/+) animals, caused small bowel ulcers in COX-1(-/-) animals. Selective inhibition of COX-1 decreased intestinal PGE(2) levels in COX-2(+/+) and COX-2(-/-) animals by 95%-97%, but caused only small bowel ulcers in the latter group. Dual inhibition of COX-1 and COX-2 in wild-type animals resulted in similar small bowel damage. Between 40% and 50% of untreated COX-2(-/-) animals had increased intestinal permeability and inflammation. Some had ileal ulcers that were distinctively different from indomethacin-induced ulcers. Furthermore, long-term celecoxib administration in wild-type animals was associated with similar damage as in the COX-2(-/-) mice. CONCLUSIONS: COX-1 deficiency or inhibition and short-term COX-2 inhibition are compatible with normal small intestinal integrity. Dual inhibition of the COX enzymes leads to damage similar to that seen with indomethacin. Long-term COX-2 deficiency or inhibition is associated with significant intestinal pathology despite normal intestinal PGE(2) levels, suggesting a role for COX-2 in the maintenance of small intestinal integrity in the mouse.