Leslie M. Higuchi

Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America.

Background: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC. Methods: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohns and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and “backwash ileitis” in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC. Results: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities. Conclusions: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms “ulcerative colitis,” “Crohn disease,” and “indeterminate colitis.” The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease

Introduction Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohns disease (CD) and ulcerative colitis (UC) are limited and conflicting. Methods We conducted a prospective study of women enrolled in the Nurses’ Health Study cohorts. Diet was prospectively ascertained every 4 years using a validated semi-quantitative food frequency questionnaire. Self-reported CD and UC were confirmed through medical record review. We examined the effect of energy-adjusted cumulative average total fat intake and specific types of fat and fatty acids on the risk of CD and UC using Cox proportional hazards models adjusting for potential confounders. Results Among 170 805 women, we confirmed 269 incident cases of CD (incidence 8/100 000 person-years) and 338 incident cases of UC (incidence 10/100 000 person-years) over 26 years and 3 317 338 person-years of follow-up. Cumulative energy-adjusted intake of total fat, saturated fats, unsaturated fats, n-6 and n-3 polyunsaturated fatty acids (PUFAs) were not associated with risk of CD or UC. However, greater intake of long-chain n-3 PUFAs was associated with a trend towards lower risk of UC (HR 0.72, 95% CI 0.51 to 1.01). In contrast, high long-term intake of trans-unsaturated fatty acids was associated with a trend towards an increased incidence of UC (HR 1.34, 95% CI 0.94 to 1.92). Conclusions A high intake of dietary long-chain n-3 PUFAs may be associated with a reduced risk of UC. In contrast, high intake of trans-unsaturated fats may be associated with an increased risk of UC.

Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses’ Health Study cohorts

Objective To examine the association between physical activity and risk of ulcerative colitis and Crohn’s disease. Design Prospective cohort study. Setting Nurses’ Health Study and Nurses’ Health Study II. Participants 194 711 women enrolled in the Nurses’ Health Study and Nurses’ Health Study II who provided data on physical activity and other risk factors every two to four years since 1984 in the Nurses’ Health Study and 1989 in the Nurses’ Health Study II and followed up through 2010. Main outcome measure Incident ulcerative colitis and Crohn’s disease. Results During 3 421 972 person years of follow-up, we documented 284 cases of Crohn’s disease and 363 cases of ulcerative colitis. The risk of Crohn’s disease was inversely associated with physical activity (P for trend 0.02). Compared with women in the lowest fifth of physical activity, the multivariate adjusted hazard ratio of Crohn’s disease among women in the highest fifth of physical activity was 0.64 (95% confidence interval 0.44 to 0.94). Active women with at least 27 metabolic equivalent task (MET) hours per week of physical activity had a 44% reduction (hazard ratio 0.56, 95% confidence interval 0.37 to 0.84) in risk of developing Crohn’s disease compared with sedentary women with <3 MET h/wk. Physical activity was not associated with risk of ulcerative colitis (P for trend 0.46). The absolute risk of ulcerative colitis and Crohn’s disease among women in the highest fifth of physical activity was 8 and 6 events per 100 000 person years compared with 11 and 16 events per 100 000 person years among women in the lowest fifth of physical activity, respectively. Age, smoking, body mass index, and cohort did not significantly modify the association between physical activity and risk of ulcerative colitis or Crohn’s disease (all P for interaction >0.35). Conclusion In two large prospective cohorts of US women, physical activity was inversely associated with risk of Crohn’s disease but not of ulcerative colitis.

Early life factors and risk of inflammatory bowel disease in adulthood.

Background:Early life factors have been postulated to play a role in development of immune tolerance and intestinal microbiome, which in turn may influence the risk of inflammatory bowel disease. Methods:We conducted a prospective cohort study of 60,186 U.S. women enrolled since 1976 in the Nurses Health Study (NHS) I and 86,495 women enrolled since 1989 in the NHS II with no history of ulcerative colitis (UC) or Crohn’s disease (CD). Information about breastfeeding, birth weight, and preterm birth were collected in 1992 in NHS I and 1991 in NHS II. Diagnoses of CD and UC were confirmed through review of medical records. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. Results:Among 146,681 women over 3,373,726 person-years of follow-up, we documented 248 cases of CD and 304 cases of UC through 2007 in NHS II and 2008 in NHS I. The median age of diagnosis was 51 for CD and 49 for UC. Compared with women who were not breastfed, women who were breastfed had multivariate-adjusted hazard ratios of 0.99 (95% confidence interval, 0.76–1.30) for CD and 1.03 (95% confidence interval, 0.81–1.32) for UC. Similarly, low or high birth weight and preterm birth were not significantly associated with risk of UC or CD. Conclusions:In 2 large prospective cohorts of U.S. women, we did not observe a significant association between early life factors including having been breastfed, birth weight, preterm birth, and risk of adult-onset UC and CD.

Zinc intake and risk of Crohn’s disease and ulcerative colitis: a prospective cohort study

BACKGROUND Diet plays a role in the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). Dietary zinc may influence risk of disease through effects on autophagy, innate and adaptive immune response and maintenance of the intestinal barrier. METHODS We analysed data from 170 776 women from the Nurses Health Study I and Nurses Health Study II, who were followed for 26 years. Zinc intake was assessed using semi-quantitative food frequency questionnaires administered every 4 years. Incident CD and UC were ascertained by medical record review. Cox proportional hazards models adjusting for potential confounders determined the independent association between zinc intake and incident disease. RESULTS Over 3 317 550 person-years (p-y) of follow-up, we identified 269 incident cases of CD and 338 incident cases of UC. Zinc intake ranged from 9 mg/day in the lowest quintile to 27 mg/day in the highest quintile. Compared with women with the lowest quintile of intake, the multivariate hazard ratios (HR) for CD were 0.92 [95% confidence interval (CI), 0.65 – 1.29) for women in the second quintile of intake, 0.60 (95% CI, 0.40 – 0.89) for the third quintile, 0.57 (95% CI, 0.38 – 0.86) for fourth quintile and 0.74 (95% CI, 0.50 – 1.10) for the highest quintile (Ptrend = 0.003). The association was stronger for dietary zinc (HR 0.63, 95% CI, 0.43 – 0.93, comparing extreme quintiles) than for zinc intake from supplements. Neither dietary nor supplemental zinc modified risk of UC. CONCLUSIONS In two large prospective cohorts of women, intake of zinc was inversely associated with risk of CD but not UC.

Inflammatory bowel disease associated with immune thrombocytopenic purpura in children

Objective Previous reports suggest an association between inflammatory bowel disease (IBD) and immune thrombocytopenic purpura (ITP) in adults. To date, only five children with both diseases have been described. The aim of the study was to describe the characteristics of children with IBD and ITP. Methods Cases were obtained from the pediatric gastroenterology community by means of the pediatric gastroenterology internet bulletin board in June 1999. Eight cases were submitted from seven medical centers. Medical records were reviewed by two pediatric gastroenterologists and a pediatric hematologist. Results The age range of the patients was 2.1 to 16.5 years, with a mean age of 9.6 ± 5.2 years. Four children had ulcerative colitis, three had Crohn disease, and one had indeterminate colitis. All had colonic involvement of IBD. Of eight patients, three had IBD first, three had ITP first, and two had both simultaneously. At ITP diagnosis, platelet count was less than 10,000/mL in five children, 17,000/mL in one child, and 50,000 to 60,000/mL in two children. Of the three children diagnosed with ITP first, two initially had rectal bleeding at the time of ITP diagnosis. Bone marrow evaluations, performed in six of eight children, were consistent with ITP. Six of the eight children had chronic ITP, including three children who were 5 years of age or younger. Therapy for ITP included steroids (n = 6), intravenous immunoglobulin (n = 6), Rh o (D) intravenous immunoglobulin (n = 2), and splenectomy (n = 1). Conclusions The authors describe the largest pediatric case series of children with IBD and ITP. More than 50% of the children had the chronic form of ITP. Most patients responded to conventional therapy for ITP and IBD.

Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn’s Disease and Ulcerative Colitis

Background Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD). Methods We conducted a prospective study of U.S. women enrolled in the Nurses’ Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case–control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFβ1 or TH17 conditions. Results Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells. Conclusion Dietary potassium is inversely associated with risk of CD with both in vitro and gene–environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.

402 Reproductive Factors and Risk of Ulcerative Colitis and Crohn's Disease: Results From Two Large Prospective Cohorts of U.S. Women

(median age 54 years) enrolled in 1976 in the Nurses Health Study without a prior history of IBD. Every two years, we have updated information on menopause status, use of postmenopausal hormone replacement therapy, and other risk factors with >90% follow-up. Self-reported CD and UC diagnoses were confirmed through medical records review by two gastroenterologists blinded to exposure information. We used Cox proportional hazards models to calculated hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age, smoking, body mass index, and type of menopause (natural vs. surgical/ radiation). We evaluated effect modification by these factors using cross-classified categories of the covariates and hormone use. We tested the significance of these interactions by using the log likelihood ratio test comparing the model with these cross-classified categories with a model that included only the potential modifiers as independent variables. Results: Through 2008, over 1,891,153 person years of follow up, we documented 138 incident cases of CD and 138 cases of UC. Compared to women who never used hormones, the multivariateadjusted HRs for UC was 1.74 (95% CI, 1.09-2.77) among women who were current users and 1.68 (95% CI, 1.05-2.71) among past users. The risk of UC increased with longer duration of hormone use (Ptrend = 0.02) and diminished with longer duration of discontinuation. Compared to current users, the multivariate-adjusted HR for UC was 2.11 (95% CI, 1.16-3.84) among women who discontinued hormones for 5 or fewer years and 1.27 (95% CI, 0.72-2.24) among women who discontinued for more than 5 years. There was no difference in the risk according to the type of hormone therapy used (estrogen vs estrogen + progesterone). In contrast, we did not observe an association between current use of hormones and risk of CD (multivariate-adjusted HR 1.19, 95% CI, 0.78-1.81). The effect of hormones on risk of UC and CDwas not modified by BMI, smoking, and type of menopause (all Pinteraction > 0.10). Conclusion: In a large prospective cohort of postmenopausal women, hormone replacement therapy was associated with an increased risk of UC but not CD. These findings may provide novel insights into biological pathways related to estrogens that may mediate the pathogenesis of UC.

1008 Reduced Sleep Duration Is Associated With an Increased Risk of Ulcerative Colitis: A Prospective Cohort Study

dl among 84 CD cases (Pdiff=.005) and 20.0 ng/dl among 91 UC cases (Pdiff=.70). Compared to women in the lowest quartile of testosterone the multivariate-adjusted RRs for CD were 0.76 (95% CI, 0.38-1.54) for women in the second quartile; 0.45 (95% CI, 0.20-0.99) for the third quartile; and 0.51 (0.24-1.10) for the highest quartile (Plinear trend = .04). We observed that for every 5 ng/dl increase in testosterone, the risk of CD decreased by 14% (Plinear trend = .03). In contrast, we did not observe any consistent association between prediagnostic testosterone and risk of UC (Plinear trend=.75). We also did not observe any association between plasma levels of SHBG and DHEAS and risk of UC or CD (all Plinear trends > .15). Conclusion: Pre-diagnosis levels of circulating total testosterone are associated with a lower risk of CD but not UC among women. The effect of testosterone in modulating innate immunity may explain this novel finding. In addition, because oral contraceptives decrease levels of endogenous testosterone, our data provides insight into the mechanism by which exogenous hormones may influence risk of CD.

1011 High Dietary Potassium Intake As Measured by 24-Hour Urine Collection Is Associated With Lower Risk of Ulcerative Colitis

dl among 84 CD cases (Pdiff=.005) and 20.0 ng/dl among 91 UC cases (Pdiff=.70). Compared to women in the lowest quartile of testosterone the multivariate-adjusted RRs for CD were 0.76 (95% CI, 0.38-1.54) for women in the second quartile; 0.45 (95% CI, 0.20-0.99) for the third quartile; and 0.51 (0.24-1.10) for the highest quartile (Plinear trend = .04). We observed that for every 5 ng/dl increase in testosterone, the risk of CD decreased by 14% (Plinear trend = .03). In contrast, we did not observe any consistent association between prediagnostic testosterone and risk of UC (Plinear trend=.75). We also did not observe any association between plasma levels of SHBG and DHEAS and risk of UC or CD (all Plinear trends > .15). Conclusion: Pre-diagnosis levels of circulating total testosterone are associated with a lower risk of CD but not UC among women. The effect of testosterone in modulating innate immunity may explain this novel finding. In addition, because oral contraceptives decrease levels of endogenous testosterone, our data provides insight into the mechanism by which exogenous hormones may influence risk of CD.