The changing epidemiology of inflammatory bowel disease (IBD) across time and geography suggests that environmental factors play a major role in modifying disease expression. Disease emergence in ...developing nations suggests that epidemiological evolution is related to westernisation of lifestyle and industrialisation. The strongest environmental associations identified are cigarette smoking and appendectomy, although neither alone explains the variation in incidence of IBD worldwide. Urbanisation of societies, associated with changes in diet, antibiotic use, hygiene status, microbial exposures and pollution have been implicated as potential environmental risk factors for IBD. Changes in socioeconomic status might occur differently in different geographical areas and populations and, consequently, it is important to consider the heterogeneity of risk factors applicable to the individual patient. Environmental risk factors of individual, familial, community-based, country-based and regionally based origin may all contribute to the pathogenesis of IBD. The geographical variation of IBD provides clues for researchers to investigate possible environmental aetiological factors. The present review aims to provide an update of the literature exploring geographical variability in IBD and to explore the environmental risk factors that may account for this variability.
Background & Aims: Mucosal healing (MH) in inflammatory bowel disease may be an important sign of efficacy of treatment and a prognostic marker of long-term disease. The aim of the study was to ...examine both the possible predictors of mucosal healing and the impact of healing on subsequent course of disease. Methods: In 740 incident patients diagnosed with ulcerative colitis (UC) or Crohn’s disease (CD) between 1990 and 1994 (before biologic therapy was available), demographics and symptoms were recorded. Clinical and endoscopic evaluations were done at baseline before treatment and repeated after 1 and 5 years in 495 patients. Results: In UC patients, education longer than 12 years and extensive disease at diagnosis were significant predictors of MH after 1 year (adjusted P = .004 and P = .02, respectively). MH was significantly associated with a low risk of future colectomy ( P = .02). In patients with CD, fever at diagnosis and medical treatment without steroids were significant predictors for MH (adjusted P = .03 and P = .01, respectively). MH was significantly associated with less inflammation after 5 years ( P = .02), decreased future steroid treatment ( P = .02). Conclusions: Several factors predicted subsequent MH. Education as predictor may implicate the importance of coping, compliance, or lifestyle. MH after 1 year of treatment is predictive of reduced subsequent disease activity and decreased need for active treatment. The present results give further strength to the use of mucosal healing as a clinical indicator and treatment goal in inflammatory bowel disease.
Objective. Cohort studies of unselected and newly diagnosed patients are essential for a better understanding of the prognosis in ulcerative colitis (UC). The aim of this study was to evaluate the ...course of UC in a population-based inception cohort during the first 10 years, and to identify prognostic risk factors based on information gathered at diagnosis. Material and methods. From 1990 to 1994, a population-based cohort of 843 patients with inflammatory bowel disease was enrolled in South-Eastern Norway. The cohort was systematically followed-up at 1, 5 and 10 years after diagnosis. Results. Of 519 patients with UC, 423 completed the 10-year follow-up, 53 died and 43 were lost to follow-up. The mortality risk was not increased compared with that in the general population. The cumulative colectomy rate after 10 years was 9.8% (95% CI: 7.4-12.4%). Initial presentation with extensive colitis and erythrocyte sedimentation rate (ESR) ≥30 mm/h was associated with an increased hazard ratio (HR) (3.57, 95% CI: 1.60-7.96) and age ≥50 years at diagnosis, with reduced HR (0.28, 95% CI: 0.12-0.65) for subsequent colectomy. Relapsing disease was noted in 83%, but half (48%) of the patients were relapse free during the last 5 years. One-fifth (69/288) of patients with proctitis or left-sided colitis had progressed to extensive colitis. Conclusions. The prognosis for UC during the first 10 years was generally good. The colectomy rate was low, and a large proportion of patients were in remission as time progressed. Patients with initially extensive colitis and elevated ESR could benefit from an early potent medical treatment strategy.
The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in ...relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims: Most studies concerning the clinical course in CD are retrospective or based on selected patient groups. Our aim was to assess the course of CD in a prospective population-based ...follow-up study and to identify possible prognostic risk factors for complications on the basis of information obtained at initial diagnosis. Methods: From 1990–1994, a population-based cohort of 843 new cases of inflammatory bowel disease was recruited in South-Eastern Norway. The cohort was systematically followed up at 1, 5, and 10 years after diagnosis. Results: Of 237 patients classified as CD, 197 completed the 10 years of follow-up, 18 died, and 22 were lost to follow-up. The cumulative relapse rate during the first 10 years was 90% (95% confidence interval, 86%–94%), and the cumulative probability of surgery was 37.9% (95% confidence interval, 31.4%–44.4%). Terminal ileal location ( P < .001), stricturing ( P = .004), penetrating behavior ( P < .001), and age younger than 40 years ( P = .03) at diagnosis were independent risk factors for subsequent surgery. A total of 53% (n = 105) of the patients had developed stricturing or penetrating disease at 10 years. A large proportion of patients (44%) were in clinical remission during the last 5 years of follow-up. Conclusions: The prognosis for CD seems better than previously reported. The probability of surgery was low, and fewer than expected developed complicated disease behavior. Nevertheless, the cumulative relapse rate of 90% and the finding of prognostic risk factors for subsequent surgery might call for attention to early effective medical treatment strategies.
TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis ...(PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants.
Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes.
Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly ...on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10−12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Patients with inflammatory bowel disease (IBD) are in general prone to weight loss. We explored the risk of inadequate gestational weight gain (GWG), and the impact of GWG on adverse pregnancy ...outcomes, among mothers with IBD in the Norwegian Mother and Child Cohort Study (MoBa).
The MoBa with 95,200 mothers enrolled from 1999 to 2008, comprised 217 mothers with ulcerative colitis and 166 with Crohn's disease. Demographics were ascertained through a basic questionnaire before the first ultrasound visit and an IBD history and disease activity during pregnancy through a questionnaire mailed out in 2013. Inadequate GWG was based on the US Institute of Medicine recommendations. The associations between IBD and inadequate GWG or adverse pregnancy outcomes were explored, adjusted for diabetes, hypertension, smoking, maternal age, education, and disease activity.
Mothers with Crohn's disease (34.3%) and ulcerative colitis (26.7%) were more frequently exposed to inadequate GWG compared with non-IBD mothers (19.4%) (adjusted odds ratio aOR = 2.02, 95% confidence interval CI, 1.42-2.86 and aOR = 1.46, 95% CI, 1.04-2.05, respectively). Mothers with IBD with inadequate GWG (exposed) had a 2-fold risk of small for gestational age infants compared with exposed non-IBD mothers (aOR = 1.93, 95% CI, 1.13-3.29). Exposed mothers with Crohn's disease and ulcerative colitis had a several-fold increased risk of small for gestational age compared with nonexposed IBD mothers (aOR = 4.5, 95% CI, 1.3-16.2, aOR = 5.5, 95% CI, 1.6-18.5). Disease activity was associated with reduced GWG (<13 kg compared with >17.5 kg) (aOR = 3.34, 95% CI, 1.33-8.38).
Inadequate GWG should be considered as a risk factor for adverse pregnancy outcomes or as a marker of disease activity.
Interleukin-33 (IL-33) is a novel member of the interleukin-1 family that induces mucosal pathology in vivo and may drive fibrosis development and angiogenesis. To address its potential role in ...inflammatory bowel disease, we explored its tissue expression in biopsy specimens from untreated ulcerative colitis patients, observing a 2.6-fold up-regulation of IL-33 mRNA levels, compared to controls. Immunohistochemical analyses of surgical specimens showed that a prominent source of IL-33 in ulcerative colitis lesions were ulceration-associated myofibroblasts that co-expressed the fibroblast marker heat shock protein 47, platelet-derived growth factor receptor (PDGFR)β, and, in part, the myofibroblast marker α-smooth muscle actin (SMA). In contrast, IL-33-positive myofibroblasts were almost absent near the deep fissures seen in Crohn's disease. A screen of known and putative activators of IL-33 in cultured fibroblasts revealed that the Toll-like receptor-3 agonist poly (I:C) was among the strongest inducers of IL-33 and that it synergized with transforming growth factor-β, a combination also known to boost myofibroblast differentiation. Experimental wound healing in rat skin revealed that the de novo induction of IL-33 in pericytes and the possible activation of scattered, tissue-resident IL-33+ PDGFRβ+ αSMA− fibroblast-like cells were early events that preceded the later appearance of IL-33+ PDGFRβ+ αSMA+ cells. In conclusion, our data point to a novel role for IL-33 in mucosal healing and wound repair and to an interesting difference between ulcerative colitis and Crohn's disease.
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