Prevalence of gastrointestinal diseases in two British national birth cohorts.

BACKGROUND: Few studies have investigated the prevalence of multiple gastrointestinal diseases in the general British population. AIM: To examine the prevalence of Crohn's disease (CD), ulcerative colitis (UC), irritable bowel syndrome (IBS), gall stones (GS), and peptic ulcer disease (PUD). SUBJECTS: The 1970 British Cohort Study (BCS70) and the National Child Development Study (NCDS) are two one week national birth cohorts born in 1970 and 1958, respectively. All cohort members living in Great Britain were interviewed in 1999/2000. METHODS: The prevalence rates of the five diseases were calculated, and associations with sex and childhood social class were investigated using logistic regression. RESULTS: At age 30 years, the prevalence rates per 10,000 (95% confidence interval (CI)) in the 1970 and 1958 cohorts, respectively, were: CD 38 (26-49), 21 (13-30); UC 30 (20-41), 27 (18-37); IBS 826 (775-877), 290 (267-330); GS 88 (71-106), 78 (62-94); and PUD 244 (214-273), 229 (201-256). There was a significantly higher proportion with CD (p=0.023) and IBS (p=0.000) in the 1970 cohort compared with the 1958 cohort at age 30 years. Comparing the cohorts in the 1999/2000 sweep, UC, GS, and PUD were significantly (p=0.001, p=0.000, p=0.000) more common in the 1958 cohort. There was a statistically significant trend for a higher risk of GS with lower social class in both cohorts combined (p=0.027). CONCLUSION: The study indicates an increasing temporal trend in the prevalence of CD and suggests a period effect in IBS, possibly due to adult life exposures or variation in recognition and diagnosis of IBS.

Siblings and the risk of inflammatory bowel disease.

BACKGROUND: Environmental exposures in early life have been implicated in the aetiology of inflammatory bowel disease (IBD). Siblings are used as proxy markers to characterize patterns of exposure relevant to the risk of IBD. METHODS: Some 15,823 patients with ulcerative colitis and 12,668 with Crohn disease from the Swedish In-patient Register were compared with 79,546 and 63,035 controls, respectively, in a case-control study. Multiple logistic regression was used to investigate associations with older and younger siblings, and adjustment was made for sex, year of birth, mother's age, region and, additionally, father's social class. RESULTS: Older siblings are associated with a graded increased risk for ulcerative colitis (P for trend <0.001) and an adjusted odds ratio of 1.15 (95% CI 1.07-1.24) for three or more older siblings. Younger siblings are associated with a graded decreased risk for Crohn disease (P for trend <0.001) with an adjusted odds ratio of 0.83 (0.76-0.90) for three or more younger siblings. The greatest protective association with Crohn disease was seen for younger siblings born within 2 years of the subject. Older maternal age is independently associated with a decreased risk of Crohn disease, with P for trend <0.001. Additional adjustment for social class did not substantially alter the results. CONCLUSIONS: Having siblings is associated with the risk and phenotype of developing IBD, possibly through their influence on patterns of antigenic exposure in early life. The association of maternal age with Crohn disease may reflect age-related changes in maternal immune profile.

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.

Potential viral pathogenic mechanism for new variant inflammatory bowel disease.

AIMS: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis. METHODS: Formalin fixed, paraffin wax embedded and fresh frozen biopsies from the terminal ileum were examined from affected children and histological normal controls. The measles virus Fusion (F) and Haemagglutinin (H) genes were detected by TaqMan reverse transcription polymerase chain reaction (RT-PCR) and the Nucleocapsid (N) gene by RT in situ PCR. Localisation of the mRNA signal was performed using a specific follicular dendritic cell antibody. RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.

Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.

There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin. Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.

Pertussis infection in childhood and subsequent type 1 diabetes mellitus.

AIMS: Pertussis has been implicated but not proven as a risk for Type 1 diabetes mellitus (DM). Previous studies have investigated paediatric, but not adult-onset Type 1 DM. We investigated association of pertussis exposures and Type 1 DM with follow-up into adulthood. METHODS: Longitudinal analysis of 16 820 members (100 with Type 1 DM) of two nationally representative British birth cohorts (the 1970 British Cohort Study (BCS70) and the National Child Development Study (NCDS)) followed from birth to ages 30 years (BCS70) and 42 years (NCDS). Cox regression analysis with age of onset for Type 1 DM as the dependent variable investigated relationships with pertussis infection and immunization, modelled as time-dependent co-variates. Simultaneous adjustment was made for Wild measles, mumps and chickenpox infections; tetanus and smallpox immunizations; sex, parental social class and cohort. The potential confounding factors were modelled as fixed co-variates. RESULTS: Cox regression analysis produced adjusted odds ratios (ORs) (with 95% confidence intervals (CIs)) of 2.21 (1.35-3.59) and 0.73 (0.49-1.05) for Type 1 DM (with onset at any age) associated with pertussis infections and immunization (trend over number of vaccinations), respectively. Adjusted ORs from Cox regression for Type 1 DM with onset after age 10 years are 2.59 (1.56-4.30) for pertussis infection and 0.63 (0.42-0.94) for pertussis immunization. None of the other infections or immunizations are notably associated with Type 1 DM. CONCLUSIONS: Some pertussis infections may be a risk for Type 1 DM and immunization may confer protection. Further research should consider delayed Type 1 DM following pertussis exposures.

Inflammatory bowel disease and laterality: is left handedness a risk?

BACKGROUND: Left handedness has been associated with inflammatory bowel disease (IBD) and autoimmune diseases. AIMS: To determine whether left handedness is associated with IBD in two prospective national birth cohorts. METHODS: Subjects with Crohn's disease (CD) and ulcerative colitis (UC) were identified from two national longitudinal birth cohorts at age 26 years (1970 British Cohort Study (BCS70), born in 1970) and age 33 years (National Child Development Study (NCDS), born in 1958). Laterality was determined at age 10 (BCS70) or seven (NCDS) years, based on hand preference for writing and foot preference for kicking a ball (BCS70 only). Multiple logistic regression was used to assess the relationship of handedness with CD, UC, and IBD in the cohorts combined and adjusted for sex. RESULTS: Both cohorts combined showed increased adjusted relative odds of 2.13 (95% confidence interval (CI) 0.97--4.65; p=0.059), 2.13 (95% CI 0.92--4.91; p=0. 077), and 2.13 (95% CI 1.20--3.78; p=0.010) for CD, UC, and IBD, respectively in left handers. CONCLUSIONS: The study suggests a link between IBD and left handedness which may be genetic and/or environmental in origin.

Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism.

OBJECTIVES: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. METHODS: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. RESULTS: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. INTERPRETATION: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.

The initial care of newborn infants and subsequent hay fever.

BACKGROUND: Patterns of neonatal exposure to microorganisms have changed substantially over the last 100 years, and it has been suggested that this has influenced the risk of immune-mediated disease. Using a proxy measure, we tested the hypothesis that the initial handling of newborn infants, which is known to affect the pattern of exposure to microorganisms, may alter the risk of developing subsequent atopy, as indicated by hay fever. METHODS: Analysis was performed on 5,519 members of the 1970 British Cohort Study, a nationally representative birth cohort. Cohort members with hay fever were identified at intervals up to the age of 26 years. Details of neonatal care and childhood circumstances were recorded prospectively. Those who had spent their first night away from their mother in the communal infant nursery were selected as likely to have experienced atypical exposure compared with infants who remained with their mother. Adjustment was made for potential confounding factors in infancy and childhood by multiple logistic regression analysis. RESULTS: Unadjusted relative odds (with 95% CI) for developing hay fever among those spending the first night in the communal nursery, when compared with other infants who remained with the mother, were 1.48 (1.23-1.77), P<0.001. Comprehensive adjustment for the potential confounding factors, including feeding practices on the first day of life, markers of social and material circumstances, and region, did not substantially alter this relationship, with adjusted relative odds of 1.31 (1.08-1.59), P=0.005. CONCLUSIONS: While our proxy measure is associated with an increased risk of hay fever, further research is required to confirm that this is due to the pattern of infectious exposure in very early life. The results are consistent with the hypothesis that the first challenges are particularly important in the development of the newborn infant's immune system.

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), Asperger's 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.

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

BACKGROUND: We previously localized beta3-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 beta3-adrenergic receptors. AIM: To identify the nature of the islet and duodenal cells that stained positive for beta3-adrenergic receptors. METHODS: Paraffin sections of human pancreas and duodenum and Chinese hamster ovary cells transfected with the human beta3-adrenergic receptor were immuno-stained for beta3-adrenergic receptors using an affinity-purified rabbit polyclonal antibody (anti-P12) raised against a 15 amino acid sequence (P12) of the human receptor. Immunohistochemical staining for the receptor was carried out in the presence and absence of P12 peptide and both somatostatin 14 and 18 peptides. beta3-adrenergic receptor-stained sections were also double-immunostained with anti-insulin, -glucagon, -somatostatin and -pancreatic polypeptide antibodies. RESULTS: A subpopulation of human pancreatic islet cells and duodenal epithelial cells expressed positive cytoplasmic beta3-adrenergic receptor immunostaining. Using distribution and double-staining techniques, these cells were found to be somatostatin-positive D cells but not A or B cells. The positive staining of D cells with anti-P12 antibody was inhibited by prior incubation of the antibody with P12 peptide but not somatostatin-14 or -28 peptides. Pancreatic vascular smooth muscle and duodenal vascular and non-vascular smooth muscle also stained with anti-P12 antibody. Transfected Chinese hamster ovary cells showed positive membrane staining. CONCLUSION: We have identified a population of neuroendocrine cells in the human pancreas and duodenum that express beta3-adrenergic receptors. These cells appear to be somatostatin D cells.

Endothelial changes precede mucosal ulceration induced by indomethacin: an experimental study in the rat.

BACKGROUND: Indomethacin has been shown to damage the villous microvasculature concomitant with alterations in villous blood flow in the rat. AIM: To test the hypothesis that alterations in blood flow result from ultrastructural damage to microvasculature endothelium. METHODS: In anaesthetized rats, jejunal villi were exteriorized in a chamber and blood flow in surface capillaries visualized by fluorescence microscopy. Villi were exposed both luminally and systemically to indomethacin (100 microg/mL) for 10 min or until blood slowing or stasis had occurred in superficial capillaries (n=3 per group). Control animals received both a luminal and intravenous vehicle for 45 min (n=3). The small intestines were vascular perfusion-fixed with 1.5% glutaraldehyde and studied by transmission electron microscopy. RESULTS: All controls appeared to be ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon the epithelium but resulted in mild endothelial vacuolization and the development of small finger-like projections into the lumen of villus surface microvasculature. At the point of blood slowing, villus tip epithelium was again normal but the endothelial vacuolization and finger-like projections became more obvious. The endothelial projections and vacuolization became severe at the point of blood stasis; this also coincided with epithelial degeneration. CONCLUSION: This study shows that villus surface microvasculature is the earliest site of morphological damage after indomethacin exposure.

Early determinants of inflammatory bowel disease: use of two national longitudinal birth cohorts.

OBJECTIVE: To examine previously cited early risk factors for inflammatory bowel disease. DESIGN: The 1946 National Survey of Health & Development (NSHD) and the 1958 National Child Development Study (NCDS) are on-going, longitudinal birth cohort studies. A nested case-control design was used combining data from both cohorts; eight controls per case, matched for gender and social class, were selected randomly. METHODS: Data concerning maternal infection in pregnancy (NCDS only), childhood infection (measles, mumps and whooping cough), birth order, appendicectomy, breast-feeding and measures of poor housing conditions in childhood were analysed. In both cohorts, the member's hospital physician or medical records were used to confirm the diagnosis. RESULTS: Twenty-six cases of Crohn's disease and 29 cases of ulcerative colitis were identified. No significant association was found between the development of Crohn's disease or ulcerative colitis and any of the studied factors. There was a trend that those with Crohn's disease were more likely not to have been breast-fed (OR 0.4, 95% CI 0.15-1.03) and not to have had an appendicectomy (OR < 1.00). The opposite was true of those with ulcerative colitis (OR 2.76, 95% CI 0.86-9.81 and OR 2.34, 95% CI 0.69-7.46, respectively). The prevalence of inflammatory bowel disease was 5.12/1000 by the age of 43 years in NSHD and 2.02-2.54/1000 by the age of 33 years in NCDS. CONCLUSIONS: The prevalence of inflammatory bowel disease in these cohorts is among the highest recorded in Europe. Childhood factors may be different for those with Crohn's disease and ulcerative colitis. These cohorts will be increasingly valuable data sources.

Similarities between ileal Crohn's disease and indomethacin experimental jejunal ulcers in the rat.

BACKGROUND: Both Crohn's disease ileal ulcers and indomethacin-induced jejunal ulcers in the rat have a predilection for the mesenteric margin of the bowel wall. Unlike the anti-mesenteric margin, the mesenteric margin is supplied by small end-arteries that might render it more sensitive to ischaemic injury. AIM: To examine, in both situations, the histological relationship between the precise localization of small bowel ulcers and the mesenteric margin. METHODS: Ileal Crohn's disease ulcers identified in surgical resection specimens (n=5) and indomethacin-induced lesions in the rat jejunum (n=6) were examined macroscopically and histologically. RESULTS: In both the human ileum and the rat jejunum, ulcers occurred consistently along the mesenteric margin, with the most extensive mucosal injury occurring at two adjacent sites on either side of the midline of this margin. At these two sites, feeding arteries entered the muscularis propria. CONCLUSIONS: For anatomical reasons apparently related to the vasculature of the human and rodent small bowel, specific sites along the mesenteric margin are susceptible to Crohn's disease ulceration and NSAID damage, respectively.

Measles vaccination and inflammatory bowel disease: a national British Cohort Study.

OBJECTIVE: Measles vaccination has been suggested as a risk for inflammatory bowel disease. Atypical age of measles infection has also been associated with Crohn's disease. This study was designed to examine the relationship of measles vaccination and age of measles vaccination with later inflammatory bowel disease. METHODS: A prospective population-based national birth cohort was used, of those born in 1 wk in April 1970 in Great Britain. The data are from 7616 responding members of the 1970 British Cohort Study with complete vaccination data, who were traced at age 26 yr. A diagnosis of Crohn's disease, ulcerative colitis, and diabetes mellitus (a control disease) was obtained by survey at age 26 yr, and confirmed by physicians. Vaccination data were from survey at age 5 yr. Measles and mumps infection data were obtained from the survey at age 10 yr. Adjustment was made for sex, household crowding in childhood, and father's social class at birth. RESULTS: No statistically significant association was found between measles vaccination status at 5 yr and Crohn's disease (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.27-1.63), ulcerative colitis (adjusted OR 0.57, 95% CI 0.20-1.61), or diabetes (adjusted OR 0.75, 95% CI 0.33-1.74). There was a statistically significant trend (p = 0.040) with increasing age of measles vaccination for risk of Crohn' s disease, although this was based on very few cases vaccinated after age 2 yr. CONCLUSIONS: In this cohort, monovalent measles vaccination status is not associated with inflammatory bowel disease by age 26 yr. Older age at measles vaccination needs to be examined in other studies to confirm whether it is a genuine risk for Crohn's disease.