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PubMed2004

Gadolinium-enhanced magnetic resonance imaging: a useful radiological tool in diagnosing pediatric IBD.

BACKGROUND: Recent advances in gadolinium-enhanced magnetic resonance imaging (G-MRI) have been developed to enhance the resolution of the intestinal mucosa and facilitate the differentiation of ulcerative colitis (UC) from Crohn's disease (CD). The objective of this study is to apply this technology in Pediatrics. METHODS: A G-MRI was performed on 58 consecutive children with suspected IBD between 1999 and 2002 using intravenous gadolinium, fat suppression, and respiration-suspended sequences to enhance the resolution of the intestinal wall. The sensitivity and specificity in diagnosing either UC or CD was determined by comparing the G-MRI to the established histologic diagnosis. RESULTS: G-MRI confirmed the diagnosis of either CD (21) or UC (7) with a sensitivity and specificity of 96% and 92%, respectively. Among the 21 patients with CD, 14 showed proximal small bowel involvement by G-MRI. In total, 17 patients were diagnosed with indeterminate colitis (IC) based on histologic criteria alone, and among these patients, G-MRI had a significantly lower non-classification rate (P < 0.02). In comparison, endoscopy was less sensitive (57%), but more specific (100%) than either histology or G-MRI in diagnosing IBD. G-MRI also showed a strong concordance with computed tomography in diagnosing CD (P = 0.001). CONCLUSION: G-MRI is a both a sensitive and specific radiologic tool in diagnosing pediatric IBD. In patients with CD, G-MRI may be useful in identifying proximal small bowel involvement. Longitudinal follow-up studies are needed in those patients diagnosed with IC to determine the predictive value of G-MRI testing.

Adolescent↗
PubMed2005

Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD.

BACKGROUND: The mucosa-associated microbiota, being very close to the inflammatory process associated with inflammatory bowel disease (IBD), may have a pathogenic role. We used a culture-independent method to analyze the mucosa-associated microbiota in IBD patients at various points of the distal digestive tract. METHODS: Thirty-five patients (20 with Crohn's disease, 11 with ulcerative colitis, and 4 controls) underwent colonoscopy. Biopsies (n = 126) were taken from 4 sites: the ileum, right colon, left colon, and rectum. Fecal samples were also obtained from 7 individuals. Temporal temperature gradient gel electrophoresis (TTGE) of 16S rDNA was used to evaluate dominant species diversity. TTGE profiles were compared using software that measures the degree of similarity. RESULTS: In a given individual, the overall similarity percentage between the 4 segments of the distal digestive tract was 94.7 +/- 4.0%, regardless of clinical status. The average similarity of all profiles for a given segment was 59.3 +/- 18.3% in the overall population. Dendrogram analysis showed that TTGE profiles did not cluster with clinical status. Differences were observed between the dominant fecal microbiota and the mucosa-associated microbiota of all 4 sites, with similarity percentages less than 92%. CONCLUSIONS: These results confirm that the dominant species differ between the mucosa-associated and fecal microbiota. They also show that, in a given individual, the microbiota is relatively stable along the distal digestive tract, showing a slight evolution in dominant species diversity from the ileum to the rectum, in both healthy subjects and patients with IBD.

Adolescent↗
PubMed2005

Interleukin-10 polymorphisms in Spanish patients with IBD.

BACKGROUND: Inflammatory bowel disease (IBD) is considered a heterogeneous, complex polygenic disease where both genetic and environmental factors are involved in the development of the disease. Interleukin-10 (IL-10) is a regulatory cytokine that might play an important role in disease pathogenesis. IL-10 contains single nucleotide polymorphisms and 2 polymorphic microsatellites in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers is associated with IBD among Spanish patients. METHODS: We genotyped 470 patients with IBD, 242 with ulcerative colitis and 228 with Crohn's disease (CD), and 572 ethnically matched controls for microsatellites IL-10R and IL-10G and 2 single nucleotide polymorphisms at positions -1082 and -819 in the proximal promoter of the gene. RESULTS: IL-10G14 microsatellite allele as well as -1082G allele were significantly increased in patients with CD. The combined presence of both alleles in 1 individual notably increased the risk to develop CD (P = 0.00006, odds ratio = 3.18). CONCLUSION: IL-10 polymorphisms contribute to susceptibility to CD in Spanish population.

Base Sequence↗
PubMed2005

IBD and skeletal health: children are not small adults!

Patients with inflammatory bowel disease often have decreased bone mass, and fragility fractures can occur. Multiple disease- and treatment related factors, including malnutrition, inflammation, malabsorption, decreased weight-bearing physical activity, and corticosteroids negatively influence bone metabolic activity. Because low-impact fracture is the pathologic expression of critically reduced bone mass and bone quality, knowing the relative risk of fractures in patients with IBD is of great interest. The absolute risk for incident fractures in these patients is still being debated. Clinical and laboratory research is clarifying mechanisms by which IBD can affect the function of osteoblasts and osteoclasts. In this concise review, we aim to provide an update on this topic, with focus on how pediatric IBD affects bone health.

Age Factors↗
PubMed2001

Lactococcus lactis, a tool for the delivery of therapeutic proteins treatment of IBD.

Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammatory diseases that consists of ulcerative colitis (UC), an inflammation of the large intestine, and Crohn's disease (CD), which can affect any part of the gastrointestinal tract. IBD affects approximately 1 in every 1000 individuals in western countries. There is a marked tendency in the age of onset toward gradually younger people. IBD represents a genuine problem in public health because of the absence of etiologic treatment. The clinical image is characterized by recurrent segmental or total inflammatory involvement of the large and/or small intestine, often resulting in a chronic, unpredictable course. The symptoms of both are extremely unpleasant and impact all aspects of quality of life. They include diarrhea, abdominal pain, rectal bleeding, fever, nausea, weight loss, lethargy, and loss of appetite. If left untreated, malnutrition, dehydration, and anemia follow, which, in extreme cases, can even lead to death. Although many patients are managed successfully with conventional medical therapy, such as anti-inflammatory corticosteroid treatment, some stay refractory to treatment, most will have recurrent activity of disease, and two thirds will require surgery. Administered orally or by injection, only a fraction of the active components of most conventional drugs reaches the intended target site, the inflamed intestinal lining. This is not only an inefficient way to deliver drugs, but, more important, means that patients are often subject to a spectrum of unpleasant side effects that result from the high levels of the drugs in other, otherwise healthy tissues and organs of the body.

Animals↗
PubMed1996

Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD).

In 153 patients with IBD, 64 with Crohn's disease (CD), and 89 with ulcerative colitis (UC), as well as in 54 healthy controls (HC), the frequencies of four known di-allelic polymorphisms in the genes for TNF-alpha and lymphotoxin alpha (LTalpha) were investigated. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF haplotypes: TNF-C, -E, -H, -I, -P. Furthermore, the relation with the presence of perinuclear anti-neutrophil cytoplasmic autoantibodies (P-ANCA) was studied. A small, but statistically significant, association between the polymorphism at position -308 in the promoter region of the TNF-alpha gene and UC was found. The frequency of the uncommon TNF-alpha -308 allele 2 was found to be decreased in patients with UC compared with HC (allele frequency of allele 2 in UC patients 0-15 versus 0.25 in HC, P=0.044). No significant differences in distribution of the TNF haplotypes were found between IBD patients and HC, although there was a tendency towards a higher frequency of the TNF-C haplotype in UC patients compared with controls (haplotype frequency 22% versus 13%; P=0.19). No statistically significant differences in distribution of the TNF haplotypes were observed between P-ANCA-positive and P-ANCA-negative UC patients. The strength of the associations indicates that TNF genes are not markers for the predisposition to suffer from IBD. They may, however, be markers of subsets of patients with UC and CD.

Adult↗
PubMed2006

A population-based case control study of potential risk factors for IBD.

BACKGROUND: We aimed to pursue potential etiological clues to Crohn's disease (CD) and ulcerative colitis (UC) through a population-based case control survey study. METHODS: Cases with CD (n = 364) and UC (n = 217), ages 18-50 yr were drawn from the population-based University of Manitoba IBD Research Registry. Potential control subjects were drawn from the population-based Manitoba Health Registry by age, gender, and geographic residence matching to the cases (n = 433). Subjects were administered a multiitem questionnaire. RESULTS: By univariate analysis, some of the variables predictive of CD included lower likelihood of living on a farm, of having drunk unpasteurized milk or having eaten pork, and UC patients were less likely to have drunk unpasteurized milk and to have eaten pork. On multivariate analysis, variables significantly associated with CD were being Jewish (OR = 4.32, 95% CI 1.10-16.9), having a first degree relative with IBD (OR = 3.07, 95% CI 1.73-5.46), ever having smoked (OR = 1.54, 95% CI, 1.06-2.25), living longer with a smoker (OR = 1.03, 95% CI, 1.01-1.04). Being a first generation Canadian (OR = 0.33, 95% CI, 0.17-0.62), having pet cats before age 5 (OR = 0.66, 95% CI, 0.46-0.96) and having larger families (OR = 0.87, 95% CI, 0.79-0.96) were protective against CD. For UC being Jewish (OR = 7.46, 95% CI, 2.33-23.89), having a relative with IBD (OR = 2.23, 95% CI, 1.27-3.9), and ever smoking (OR = 1.62, 95% CI, 1.14-2.32) were predictive. CONCLUSION: This study reinforced the increased risk associated with family history, being Jewish, and smoking history, however, a number of significant associations with CD and UC on univariate and multivariate analysis may support the "hygiene hypothesis" and warrant further exploration in prospective studies.

Adolescent↗
PubMed2006

Do guidelines matter? Implementation of the ACG and AGA osteoporosis screening guidelines in inflammatory bowel disease (IBD) patients who meet the guidelines' criteria.

OBJECTIVE: The American College of Gastroenterology (ACG) and American Gastroenterology Association (AGA) have both recently issued guidelines (the "Guidelines") regarding the diagnosis and management of osteoporosis in patients with inflammatory bowel disease (IBD). The objective of this study was to determine the yield of implementing the Guidelines' recommendations in a prospective cohort of IBD patients and identify the prevalence of bone loss, risk factors, and potential influence on management. METHODS: One hundred consecutive IBD patients who fulfilled the Guidelines' criteria underwent dual energy X-ray absorptiometry scanning (DEXA) scanning of the lumbar vertebrae and bilateral hips. Demographic data, risk factor information, and changes in therapy based on screening were collected and analyzed. RESULTS: Indications for screening were history of prolonged past or concurrent steroid use (92%), postmenopausal status (7%), and history of low trauma fracture (7%). Forty-four percent of patients had osteopenia of either the lumbar spine or the hips, 12% had osteoporosis of either the spine or hips, and 44% had normal bone density. In a univariate analysis, factors predicting a greater likelihood of osteoporosis (but not osteopenia) were a diagnosis of Crohn's disease (vs. ulcerative colitis), low body mass index in women, and postmenopausal status. Specific therapies based on DEXA findings were initiated in 69% of patients: oral calcium and vitamin D supplementation in 69% and an oral bisphoshphonate in 20%. CONCLUSIONS: Implementation of the Guidelines led to the detection of osteopenia or osteoporosis and initiation of specific therapies in a majority of patients who met the Guidelines' criteria for DEXA screening.

Absorptiometry, Photon↗
PubMed2005

Psychological stress in IBD: new insights into pathogenic and therapeutic implications.

Psychological stress has long been reported anecdotally to increase disease activity in inflammatory bowel disease (IBD), and recent well designed studies have confirmed that adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with quiescent IBD. This evidence is increasingly supported by studies of experimental stress in animal models of colitis. With the evolving concept of psychoneuroimmunology, the mechanisms by which the nervous system can affect immune function at both systemic and gut mucosal levels are gradually becoming apparent. Recent data suggest that stress induced alterations in gastrointestinal inflammation may be mediated through changes in hypothalamic-pituitary-adrenal (HPA) axis function and alterations in bacterial-mucosal interactions, and via mucosal mast cells and mediators such as corticotrophin releasing factor (CRF). To date, the therapeutic opportunities offered by stress reduction therapy remain largely unexplored, in part because of methodological difficulties of such studies. This paper reviews recent advances in our understanding of the pathogenic role of psychological stress in IBD and emphasises the need for controlled studies of the therapeutic potential of stress reduction.

Acute Disease↗
PubMed1980

Passively transferred immunity to IBD following live vaccination of parent chickens by two different routes.

Vaccination of broiler breeder parents with live infectious bursal disease (IBD) vaccine by the oral route resulted in higher and more persistent quantitative gel diffusion precipitins than vaccination by intramuscular injection. All the progeny of the orally vaccinated parents had maternally derived IBD antibody (MDA) at hatching while MDA was detected in only 35 per cent of the progeny of the intramuscularly vaccinated parents. This MDA had disappeared completely at 14 and eight days respectively. Susceptibility to IBD challenge began at eight days in the first group and at one day old in the second. The age of 100 per cent susceptibility occurred at 19 and 11 days in the respective groups.

Administration, Oral↗
PubMed2002

T cell receptor delta repertoire in inflamed and noninflamed colon of patients with IBD analyzed by CDR3 spectratyping.

Gamma/delta T cells might play an important role in autoimmune conditions like inflammatory bowel disease (IBD). In the present study, we characterized the T cell receptor (TCR)-delta repertoire by complementarity determining region 3 (CDR3) spectratyping in the inflamed and noninflamed mucosa and in the peripheral blood of subjects with Crohn's disease and ulcerative colitis. In contrast to previously published data about alpha/beta T cells, we rarely found oligoclonal expansions of gamma/delta T cells specific only for the inflamed mucosa. The same dominant gamma/delta T cell expansions were also present in the noninflamed colon. Furthermore, the peripheral gamma/delta TCR repertoire was oligoclonal but clearly distinct from that in the inflamed intestine. Thus our results do not support a role for antigen-specific gamma/delta T cells in IBD, and dominant gamma/delta T cells of the peripheral blood are not likely to be derived from the inflamed gut. However, in several patients, the TCR-delta-repertoire was highly diversified, whereas in others we observed a loss of dominant gamma/delta T cell clones when inflamed and noninflamed mucosa were compared. In conclusion, those changes indicate that gamma/delta T cells might play an important role in a subset of patients with IBD.

Amino Acid Sequence↗
PubMed2003

Heterogeneity in IBD allele sharing among covariate-defined subgroups: issues and findings for affected relatives.

OBJECTIVES: Modelling of variation in identical-by-descent (IBD) allele sharing using covariates can increase power to detect linkage, identify covariate-defined subgroups linked to particular marker regions, and improve the design of subsequent studies to localize genes and characterize their effects. In this report, we highlight issues that arise in studies of families with affected relatives. METHODS: Mirea et al. [Genet Epidemiol 2003, in press] extended linear and exponential linkage likelihood models [Kong and Cox, Am J Hum Genet 1997;61: 1179-1188] to model variation in NPL scores among covariate-defined groups of families, and proposed likelihood ratio (LR) and t statistics to detect differences in allele sharing between groups defined by a binary covariate. Here we evaluate factors affecting the power of these tests analytically and by example, as well as effects of constraints, nuisance parameters, and incomplete data on test validity by simulation of locus heterogeneity in families with affected siblings or affected cousins. RESULTS: Provided constraints on the parameters are avoided, these tests are particularly useful when one subgroup has less than expected IBD sharing. The distribution of the LR statistic depends on the extent of linkage, particularly in the presence of constraints. The t statistic may be biased by group differences in information content. CONCLUSIONS: We recommend that constraints be applied cautiously, and covariate effects in IBD allele sharing models interpreted with care.

Alleles↗
PubMed2003

Genome sharing in large pedigrees: multiple imputation of ibd for linkage detection.

Our objective is the development of robust methods for assessment of evidence for linkage of loci affecting a complex trait to a marker linkage group, using data on extended pedigrees. Using Markov chain Monte Carlo (MCMC) methods, it is possible to sample realizations from the distribution of gene identity by descent (IBD) patterns on a pedigree, conditional on observed data YM at multiple marker loci. Measures of gene IBDW which capture joint genome sharing in extended pedigrees often have unknown and highly skewed distributions, particularly when conditioned on marker data. MCMC provides a direct estimate of the distribution of such measures. Let W be the IBD measure from data YM, and W* the IBD measure from pseudo-data Y*M simulated with the same data availability and genetic marker model as the true data YM, but in the absence of linkage. Then measures of the difference in distributions of W and W* provide evidence for linkage. This approach extracts more information from the data YM than either comparison to the pedigree prior distribution of W or use of statistics that are expectations of W given the data YM. A small example is presented.

Chromosome Mapping↗
PubMed2001

Serologic markers in inflammatory bowel disease (IBD).

Inflammatory bowel disease (IBD) is a generic term that refers to Crohn's disease and ulcerative colitis. Crohn's disease (CD) is a granulomatous enteritis which can involve the ileum, colon, and other parts of the intestinal tract. The serologic responses seen in Crohn's disease include antibodies to Saccharomyces cerevisiae, mycobacteria, bacteroides, listeria and E. coli. Many of these organisms may be involved in the pathogenesis of the Crohn's disease. Ulcerative colitis is characterized by inflammation of the mucosa and submucosa of the large intestine. The CD and UC are considered to be distinct forms of IBD; however, there is a subgroup of CD with a UC-like presentation. In recent years, several serologic markers have been found to be useful for the diagnosis and differentiation of CD and UC. These markers include the following antibodies (a) 2pANCA, (b) ASCA, (c) pancreatic antibody, and (d) OmpC antibody. The application of a panel of markers with the use of an algorithm can identify specific subtypes of IBD that have different clinical courses and progression of the diseases. The application of the serologic markers is useful for diagnosis and management of CD and UC patients.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1986

Immunoglobulins (Ig) in circulating immune complexes (CIC) in cancer and inflammatory bowel disease (IBD).

Chronically inflamed tissues and most malignancies have antigenic properties. Patients with long-standing inflammatory bowel disease (IBD) are prone to development of colorectal cancer, which is known to shed antigens in the bloodstream. In an effort to study immunological aspects of these diseases, sera from patients with IBD and colorectal cancer were evaluated for presence of circulating antigen-antibody immune complexes (CIC), and compared to normal controls. CIC were precipitated by polyethylene glycol (PEG) and found to be elevated in all diseased groups. Dissociation of CIC and quantification of their antibody component revealed significant elevation of each immunoglobulin in IBD and in patients with colorectal cancer versus control: IgG = 1.776 +/- 1.573 vs 0.734 +/- 0.618 (P less than 0.001); IgA = 0.368 +/- 0.452 vs 0.090 +/- 0.198 (P less than 0.001); IgM = 0.434 +/- 0.235 vs 0.080 +/- 0.285 (P less than 0.001) serum total Ig levels were consistently much higher than CIC Ig. No correlation was found between the individual serum Ig components and the precipitable complexes-bound Ig, suggesting a selective recognition of antigenic components in the CIC, rather than non-specific association and subsequent precipitation of serum Ig. CIC may represent an easily accessible source of immunological determinants for the study of malignant and chronic inflammatory diseases.

Adolescent↗
PubMed1991

Affected kin-pair IBD methods: genetic models.

Cases of interest using affected sib-pair methods to distinguish between recessive and additive (dominant) modes of inheritance of a disease-predisposing gene involve goodness-of-fit tests with a small expected number in the "share-zero parental haplotypes" category, as well as an unknown parameter, the frequency of the disease-predisposing allele. Our simulations demonstrate that the real significance level of the chi-square test using the three-haplotype-sharing IBD values (share 2, 1, and 0 parental haplotypes) is close to the assumed (.05) level in these cases, so that the haplotype-sharing classes do not have to be lumped, which would leave no degrees of freedom for a statistical test. The validity of the chi-square approximation in cases of small expected frequencies has previously been described, but the situations that have been considered do not cover the very small values in the share-zero category that are often expected in the affected sib-pair analysis, nor do they involve estimation of an unknown parameter. Although including IBD values from affected kin pairs other than sibs can be a very powerful tool in demonstrating linkage of a marker and disease, these pairs do not add power, in fact they reduce the power, of the chi-square tests of goodness-of-fit of modes of inheritance.

Alleles↗
PubMed1998

Endothelial ligands and homing of mucosal leukocytes in extraintestinal manifestations of IBD.

Crohn's disease and ulcerative colitis are quite often complicated with manifestations in extraintestinal organs like joints, eye, and skin. Although the etiopathogenesis of these nonmucosal complications remains unsettled, they all share the characteristic feature of inappropriate leukocyte recruitment in nonlymphatic organs. Under normal conditions, lymphocytes recirculate between the blood and lymphoid organs in search of their cognate antigens, whereas polymorphonuclear leukocytes are excluded from tissues. On inflammation, the leukocyte trafficking changes dramatically. Granulocytes infiltrate into the inflammatory focus very rapidly, and they are followed by lymphocytes, especially activated immunoblasts and memory cells, which now also leave the vasculature at nonlymphoid tissues. Leukocyte extravasation from the blood into the tissue is a multistep process governed by sequential interactions between adhesion molecules expressed on the surface of leukocytes and their ligands on the luminal side of the endothelial cells lining the vessels. In this review, we describe the recirculation routes of mucosal lymphocytes in physiologic conditions, as well as the changes seen in mucosal and extramucosal homing in inflammatory bowel disease (IBD). We present a working model of how adhesive molecular interactions between mucosal immune cells and endothelial cells may explain the pathogenesis of the development of inflammatory cell infiltrate in distant organs in IBD, and how this information may help to plan new antiadhesive therapeutic strategies.

Animals↗
PubMed2006

Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients.

In Crohn's disease the optimal duration of azathioprine treatment is still controversial and for ulcerative colitis only limited data are available to support its efficacy. Charts of 1176 patients with IBD from 16 European centers were analyzed. Flare incidences and steroid dosages were assessed for the time before and during treatment and after discontinuation. Within the first 4 years, azathioprine suppressed flare incidence and steroid consumption in both diseases (P < 0.001). While in CD discontinuation after 3-4 years did not lead to reactivation, this was the case in UC. However, continuation beyond 4 years further improved clinical activity in CD and steroid requirement in both diseases (P < 0.001). Discontinuation of azathioprine may thus be considered after 3-4 years in CD patients in complete remission without steroid requirement. In all other CD patients and for UC patients in general, continuation seems beneficial. These results support a novel differential algorithm for long-term azathioprine therapy in IBD.

Adult↗