Andrew Anthony

Enterocolitis in children with developmental disorders

OBJECTIVE:Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls.METHODS:Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3–16; 53 male). Developmental diagnoses were autism (50 patients), Aspergers syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0–3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2–13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely.RESULTS:Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001).CONCLUSIONS:A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.

Retraction of an interpretation

This statement refers to the Early Report “Ileal-lymphoidnodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children”, published in The Lancet in 1998. It is made by 10 of the 12 original authors who could be contacted. It should be noted that this statement does not necessarily reflect the views of the other co-authors. The main thrust of this paper was the first description of an unexpected intestinal lesion in the children reported. Further evidence has been forthcoming in studies from the Royal Free Centre for Paediatric Gastroenterology and other groups to support and extend these findings. While much uncertainty remains about the nature of these changes, we believe it important that such work continues, as autistic children can potentially be helped by recognition and treatment of gastrointestinal problems. We wish to make it clear that in this paper no causal link was established between MMR vaccine and autism as the data were insufficient. However, the possibility of such a link was raised and consequent events have had major implications for public health. In view of this, we consider now is the appropriate time that we should together formally retract the interpretation placed upon these findings in the paper, according to precedent. We were unable to contact John Linnell.

Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism.

We have reported lymphocytic colitis in children with regressive autism, with epithelial damage prominent. We now compare duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation and 18 histologically normal controls. Immunohistochemistry was performed for lymphocyte and epithelial lineage and functional markers. We determined the density of intraepithelial and lamina propria lymphocyte populations, and studied mucosal immunoglobulin and complement C1q localisation. Standard histopathology showed increased enterocyte and Paneth cell numbers in the autistic children. Immunohistochemistry demonstrated increased lymphocyte infiltration in both epithelium and lamina propria with upregulated crypt cell proliferation, compared to normal and cerebral palsy controls. Intraepithelial lymphocytes and lamina propria plasma cells were lower than in coeliac disease, but lamina propria T cell populations were higher and crypt proliferation similar. Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.

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.

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 TNFα, IL-2, IL-4, IFNγ, 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+TNFα+ 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+IFNγ+, 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+TNFα+ and CD3+IFNγ+ 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+TNFα+ 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 Crohns 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 Crohns disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohns, and normal patients were H. pylori negative.METHODS:Snap-frozen antral biopsies were stained for CD3, CD4, CD8, γδ 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 Crohns 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, Crohns 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 Crohns disease, which is not CD8-dominated. As in the small intestine, there is epithelial deposition of IgG.

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.

Beta(beta)3-adrenergic receptors in human pancreatic islet and duodenal somatostatin neuroendocrine cells.

We previously localized β3‐adrenergic receptors immunohistochemically in human gastrointestinal smooth muscle and incidently found a population of human pancreatic islet cells and duodenal epithelial neuroendocrine cells that also expressed β3‐adrenergic receptors.

Retraction: Enterocolitis in Children With Developmental Disorders

On 28 January 2010, the UK General Medical Council’s Fitness to Practice Panel raised concerns about a paper published in the Lancet by Dr Wakefi eld et al. (1). Th e main issues were that the patient sample collected was likely to be biased and that the statement in the paper, that the study had local ethics committee approval, was false. Th ere was also the possibility of a serious confl ict of interest in the interpretation of the data. Th e Lancet has now retracted this paper (1). Th is paper in the American Journal of Gastroenterology (AJG) (2) also includes the 12 patients in the original Lancet article and therefore we retract this AJG paper from the public record.