Long-term behavior and functional outcomes of ileal-pouch anal anastomosis in inflammatory bowel disease with changing phenotype.

BACKGROUND: Ileal-pouch-anal anastomosis is the operation of choice after proctocolectomy for ulcerative colitis; some patients will develop Crohn's disease. We aim to determine long-term behavior and outcomes of inflammatory bowel disease-ileal-pouch-anal anastomosis after colectomy, where a specialist gastrointestinal pathologist re-evaluated the initial colectomy specimen. METHODS: Patients with inflammatory bowel disease-ileal-pouch-anal anastomosis were identified from a single-surgeon prospective database containing 1,165 patients accrued from 1991 to 2017 and invited to complete pouch-function and quality-of-life assessments. Medical records were used to obtain clinical outcomes and subjective functional assessments for those unable to be contacted. Data were compared between patients with and without histological assessment disagreement and subsequent inflammatory bowel disease behavior subgroups. RESULTS: For 138 patients included in the analysis, the median follow-up was 22.5 (range: 5-39) years. A total of 39.1% of patients had histologic diagnostic change after gastrointestinal pathologist review, and 19% and 39% developed Crohn's disease-like disease behavior at 10- and 20-year follow-ups. Pouch function and quality-of-life scores were similar across diagnostic change subgroups. Pouch failure was higher in Crohn's-like disease (31.1 vs 13.0%, P < .05). Intestinal continuity was maintained in 68.9% of Crohn's disease-like patients, 57.9% required biologics. Gastrointestinal pathologist review did not alter the time to new diagnosis (P = .419) or time to pouch failure (P = .320), mean: 11.0 and 11.41 years, respectively. CONCLUSION: We describe equivocal patient-reported outcomes in patients with ileal-pouch-anal anastomosis and changing histologic and clinical diagnosis. Although pouch excision and biologic use rates are higher, many Crohn's disease-like patients maintain their pouch. Diagnostic change and pouch failure often occur >10 years after ileal-pouch-anal anastomosis creation. This supports the consideration of ileal-pouch-anal anastomosis after colectomy in carefully selected patients with inflammatory bowel disease, even those with ambiguous histology and the need for close long-term follow-up.

Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma.

BACKGROUND: Colon cancer survival is dependent on metastatic potential and treatment. Large RNA-sequencing data sets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE: This study aimed to identify a highly specific biomarker for overall survival in colon adenocarcinoma by using an RNA-sequencing data set. DESIGN: Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n = 271) were downloaded from The Cancer Genome Atlas. A binomial regression model was used to calculate differential RNA expression between paired colon cancer and normal epithelium samples (n = 40). Highly differentially expressed RNAs were examined. SETTINGS: This study was conducted at the University of Louisville using data acquired by The Cancer Genome Atlas. PATIENTS: Patients from US accredited cancer centers between 1998 and 2013 were analyzed. MAIN OUTCOME MEASURES: The primary outcome measures were recurrence-free and overall survival. RESULTS: The median age was 66 years (147/271 men, 180/271 White patients). Thirty RNAs were differentially expressed in colon adenocarcinoma compared with paired normal epithelium, using a log-fold change cutoff of ±6. Using median expression as a cutoff, 4 RNAs were associated with worse overall survival: decreased ZG16 (log-rank = 0.023), aquaporin 8 (log-rank = 0.023), and SLC26A3 (log-rank = 0.098), and increased COL1A1 (log-rank = 0.105). On multivariable analysis, low aquaporin 8 expression (HR, 1.748; 95% CI, 1.016-3.008; p = 0.044) was a risk factor for worse overall survival. Our final aquaporin 8 model had an area under the curve of 0.85 for overall survival. On subgroup analysis, low aquaporin 8 was associated with worse overall survival in patients with high microsatellite instability and in patients with stage II disease. Low aquaporin 8 expression was associated with KRAS and BRAF mutations. Aquaporin 8 immunohistochemistry was optimized for clinical application. LIMITATIONS: This was a retrospective study. CONCLUSION: Aquaporin 8 is a water channel selectively expressed in normal colon tissue. Low aquaporin 8 expression is a risk factor for worse overall survival in patients who have colon cancer. Aquaporin 8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance. See Video Abstract at http://links.lww.com/DCR/B603. LA DISMINUCIN DE LA EXPRESIN TUMORAL DE LA ACUAPORINA DEL CANAL DE AGUA ESPECFICO DEL COLON SE ASOCIA CON UNA REDUCCIN DE LA SUPERVIVENCIA GENERAL EN EL ADENOCARCINOMA DE COLON: ANTECEDENTES:La supervivencia del cáncer de colon depende del potencial metastásico y del tratamiento. Grandes conjuntos de datos de secuenciación de ARN pueden ayudar a identificar biomarcadores específicos del cáncer de colon para mejorar los resultados de los pacientes.OBJETIVO:Identificar un biomarcador altamente específico para la supervivencia general en el adenocarcinoma de colon utilizando un conjunto de datos de secuenciación de ARN.DISEÑO:La secuenciación de ARN sin procesar y los datos clínicos para pacientes con adenocarcinoma de colon (n = 271) se descargaron de The Cancer Genome Atlas. Se utilizó un modelo de regresión binomial para calcular la expresión diferencial de ARN entre muestras de cáncer de colon emparejadas y muestras de epitelio normal (n = 40). Se examinaron los ARN expresados de forma altamente diferencial.ENTORNO CLINICO:Este estudio se realizó en la Universidad de Louisville utilizando datos adquiridos por The Cancer Genome Atlas.PACIENTES:Se analizaron pacientes de centros oncológicos acreditados en Estados Unidos entre 1998-2013.PRINCIPALES MEDIDAS DE VALORACION:Las principales medidas de valoración fueron la supervivencia general y libre de recurrencia.RESULTADOS:La mediana de edad fue de 66 años (147/271 hombres, 180/271 caucásicos). Treinta ARN se expresaron diferencialmente en el adenocarcinoma de colon en comparación con el epitelio normal emparejado, utilizando un límite de cambio logarítmico de ± 6. Utilizando la expresión mediana como punto de corte, cuatro ARN se asociaron con una peor supervivencia general: disminución de ZG16 (rango logarítmico = 0,023), acuaporina8 (rango logarítmico = 0,023) y SLC26A3 (rango logarítmico = 0,098) y aumento de COL1A1 (log -rango = 0,105). En el análisis multivariable, la baja expresión de acuaporina8 (HR = 1,748, IC del 95%: 1,016-3,008, p = 0,044) fue un factor de riesgo para una peor supervivencia global. Nuestro modelo de aquaporin8 final tuvo un AUC de 0,85 para la supervivencia global. En el análisis de subgrupos, la acuaporina8 baja se asoció con una peor supervivencia general en pacientes con MSI-H y en pacientes en estadio II. La baja expresión de acuaporina8 se asoció con mutaciones de KRAS y BRAF. La inmunohistoquímica de aquaporina8 se optimizó para su aplicación clínica.LIMITACIONES:Este fue un estudio retrospectivo.CONCLUSIÓN:La acuaporina8 es un canal de agua expresado selectivamente en el tejido normal del colon. La baja expresión de AQP8 es un factor de riesgo de peor supervivencia global en pacientes con cáncer de colon. La medición de aquaporina8 puede tener un papel como un biomarcador de pronóstico específico del colon y ayudar en la estratificación del riesgo del paciente para una mayor vigilancia. Consulte Video Resumen en http://links.lww.com/DCR/B603.

Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.

BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. METHODS: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSIONS: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

Long-term outcomes following ileal pouch-anal anastomosis in patients with indeterminate colitis.

BACKGROUND: The advisability of performing ileal pouch-anal anastomosis for patients with indeterminate colitis is debated. Indeterminate colitis is found in up to 15% of inflammatory bowel disease colectomy specimens. We determined long-term outcomes in patients diagnosed with indeterminate colitis undergoing ileal pouch-anal anastomosis. METHODS: Fifty-six patients were included with a mean follow-up of 14 ± 7 years. Long-term behavior was defined based on surgeon assessment as "Crohn disease-like" in patients who subsequently developed clear signs of Crohn disease and as "non-Crohn disease-like." Long-term function was assessed using the Cleveland Global Quality of Life and Pouch Functional Score. RESULTS: Thirty-nine percent of patients developed Crohn disease-like behavior, and 61% developed non-Crohn disease-like behavior. Both groups experienced a high rate of pouchitis (57%). Crohn disease-like patients required more anti-inflammatory/immunomodulatory medications (95% vs 18%, P < .001), dilatations for afferent-limb strictures (41% vs 0%, P < .001), and pouch reoperations (32% vs 6%, P = .02). Eight patients required pouch excision or diversion (7 with Crohn disease-like behavior). The Pouch Functional Score was equivalent between groups. CONCLUSION: Long-term function after ileal pouch-anal anastomosis for the majority of indeterminate colitis patients was good. Approximately 40% eventually exhibited Crohn disease-like behavior, but the majority had acceptable function and quality of life. Ileal pouch-anal anastomosis is an appropriate surgical option for indeterminate colitis patients after informed consent.

A simple tissue-handling technique performed in the endoscopy suite improves histologic section quality and diagnostic accuracy for serrated polyps.

BACKGROUND AND STUDY AIMS: Surveillance intervals after colonoscopic resection of serrated polyps are partially predicated on the histology of the polyp(s) removed during the index exam. Histologic discrimination between sessile serrated adenomas/polyps (SSA/P) and hyperplastic polyps is challenging. We devised and tested a simple tool--an envelope--that gastroenterologists can integrate into routine colonoscopy practice to address this problem. METHODS: In the "modified protocol," immediately after polypectomy each serrated polyp was flattened and enclosed in a paper envelope before being placed in formalin. In the pathology laboratory, each polyp was sectioned after processing. A two-site, prospective, randomized, single-blinded trial was performed to compare this modified protocol with the conventional protocol. Serrated polyps located proximal to the splenic flexure and 5-20 mm in diameter were included. A novel orientation score that measured the number of well-oriented crypts per unit area of polyp (higher orientation score = better orientation) was validated. Orientation score, SSA/P diagnosis rate, and inter-pathologist agreement were measured. RESULTS: A total of 375 polyps were enrolled, of which 264 were identified for analysis. The mean orientation scores in the modified and conventional protocol groups were 3.11 and 1.13, respectively (P < 0.0001). SSA/Ps were diagnosed in 103/135 cases (76.3%) in the modified protocol group vs. 54/129 (41.9%) in the conventional protocol group (P < 0.0001). Inter-pathologist agreement was higher with the modified than the conventional protocol (77.0% vs. 62.8%; P = 0.015). CONCLUSION: Standard polyp handling techniques may be sub-optimal for interpretation of serrated polyps resected at colonoscopy, and may lead to inadvertent histologic "under-grading" of many lesions. Our intervention improved histopathologic interpretation and increased the SSA/P diagnosis rate.

Clinical predictors of inflammatory bowel disease in a genetically well-defined Caucasian population.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. The objective of this study is to examine the combined gene-environment interactions influencing IBD susceptibility in a well-defined Caucasian cohort in rural mid-America. METHODS: Patients were diagnosed to have CD or UC using conventional radiologic, endoscopic, and/or histopathologic findings. Histological diagnosis was made by a single specialist gastrointestinal pathologist with a particular interest in IBD. Information regarding cigarette smoke exposure was obtained by administration of the Behavioral Risk Factor Surveillance System Survey (BRFSS) to all patients. Genomic DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 Single Nucleotide Polymorphisms (SNP) in NOD2, IL23r, OCTN1 genes along with IGR. RESULTS: Our cohort consists of 1196 patients: 435 controls, 485 CD patients, and 276 UC patients. Only patients with genotype data for at least 7 of 11 SNPs were included in our data analysis. The control groups for all 11 SNPs were in Hardy-Weinberg Equilibrium. In genotype-association SNP analysis, all NOD2 SNPs (rs5743293, rs2066844, rs2066845) and the IL23r SNP (rs11465804) showed a significant association to IBD (p < 0.03). A multiple gene-interaction analysis showed an association between NOD2 and IL23r with UC (p = 0.04). There were no associations between any OCTN1 and IGR SNPs and IBD in this cohort. A multivariable logistic regression analysis showed that female gender, "current" or "former" smoking status, family history of IBD, and NOD2 SNP minor alleles were associated with CD. CONCLUSION: IBD remains to be challenging to properly diagnose, characterize, and treat. Our study proposes a combined genetic, phenotypic, and environmental approach in an attempt to better understand IBD. Previously demonstrated associations between OCTN1 and IGR and IBD were not confirmed.

Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer.

One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines.

Pathology of inflammatory bowel disease.

Inflammatory bowel disease in childhood refers to ulcerative colitis, Crohn's disease, and colitis of an indeterminate type. Their gross and microscopic features are discussed along with the differential diagnosis from other childhood conditions associated with bloody diarrhea.

Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma.

BACKGROUND: N-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD. METHODS: A case control study was performed with 729 Caucasian participants, 123 CRC, 201 CD, 167 UC, 15 IBD dysplasia/cancer and 223 controls. NAT1 and NAT2 genotyping were performed using Taqman based techniques. Eight single nucleotide polymorphisms (SNPs) were characterized for NAT1 and 7 SNPs for NAT2. Haplotype frequencies were estimated using an Expectation-Maximization (EM) method. Disease groups were compared to a control group for the frequencies at each individual SNP separately. The same groups were compared for the frequencies of NAT1 and NAT2 haplotypes and deduced NAT2 phenotypes. RESULTS: No statistically significant differences were found for any comparison. Strong linkage disequilibrium was present among both the NAT1 SNPs and the NAT2 SNPs. CONCLUSION: This study did not demonstrate an association between NAT1 and NAT2 polymorphisms and IBD or sporadic CRC, although power calculations indicate this study had sufficient sample size to detect differences in frequency as small as 0.05 to 0.15 depending on SNP or haplotype.

Emerging eosinophilic (allergic) esophagitis: increased incidence or increased recognition?

CONTEXT: Eosinophilic esophagitis is a disease of the esophagus with distinct histologic features (prominent intraepithelial eosinophils, particularly superficial with clustering) and characteristic endoscopic features (trachealization, white plaques). The presence of intraepithelial eosinophils had been recognized since 1982 as indicative of reflux esophagitis but little attention was initially paid to their numbers or location. Eosinophilic esophagitis has been recently described and there have been a number of reports that its incidence is on the rise. It had been our impression that eosinophilic esophagitis was being seen more frequently, perhaps resulting from some environmental change. OBJECTIVE: To investigate the increased prevalence of eosinophilic esophagitis. DESIGN: We analyzed a similar group of cases from 2005 (n = 150) as compared with 1990 (n = 115). Consecutive patients with mucosal esophageal biopsies from May through June of the respective years were included in the analysis. Patients with Barrett metaplasia or with carcinoma were excluded. The highest density of intraepithelial eosinophils for each patient was recorded as the number of intraepithelial eosinophils per single high-power field. The patients were categorized by the number of intraepithelial eosinophils per high-power field with those cases with greater than 20 intraepithelial eosinophils per high-power field representing eosinophilic esophagitis. RESULTS: There was no difference in the incidence of eosinophilic esophagitis between 1990 and 2005. CONCLUSIONS: The apparent increased incidence of eosinophilic esophagitis is largely a result of an increase in recognition rather than an increase in disease resulting from an environmental factor.

CARD15 genotype-phenotype relationships in a small inflammatory bowel disease population with severe disease affection status.

Inflammatory bowel disease (IBD; MIM# 266600) is subdivided on the basis of clinical findings as either Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Three previously described mutations within the IBD susceptibility gene CARD15 (R702W, G908R, 1007fs) increase susceptibility to CD with a terminal ileal and/or ileocolonic location and fibrostenosing behavior. We undertook an association study using 477 unrelated IBD patients (248 CD, 172 UC, 57 IC) and 104 population controls to determine whether these previously described associations could be replicated in a small, accurately phenotyped cohort. Case-control and family-based approaches were employed to analyze CARD15 mutant allele and haplotype data. Analyses were initially performed in unstratified IBD cohorts. The R702W mutant allele was associated with CD on case-control analysis (q=0.036, P=.004), and 1007fs with CD on pedigree disequilibrium testing (P=.020). All 3 CARD15 mutations increased susceptibility to a variety of CD subphenotypic manifestations, including early-onset CD in individuals with a family history of IBD, and CD complicated by extraintestinal disease. We also present evidence to suggest that R702W may predispose to a more generalized form of CD. Additionally, we confirm that CARD15 mutations are associated with terminal ileal/ileocolonic, and to a lesser extent, fibrostenosing CD.

Chronic pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: effect on quality of life.

Chronic pouchitis can be observed in up to 30% of patients after proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). It remains a poorly understood complication and often requires chronic antibiotic and antidiarrheal treatment. We hypothesized that its occurrence can be predicted by distinct clinical parameters and that it adversely affects quality of life. Sixty-eight of 129 consecutive UC patients who underwent IPAA over a 10-year period were evaluated by Cleveland Clinic Global Quality of Life questionnaires, telephone interviews, and by chart review. Using bivariate comparison, clinical predictors for the occurrence of chronic pouchitis were sought, and postoperative data analyzed with regard to functional results and quality of life. Nineteen of 68 patients (28%) experienced chronic pouchitis, but its occurrence could not be predicted by any variable assessed. Patients with chronic pouchitis complained of more frequent fecal incontinence (32% vs. 4% in controls; P < 0.01), of more frequent bowel movements (7.7/day vs. 6.2/day; P < 0.05), and experienced severe abdominal pain more often (P < 0.05). Overall quality of life and satisfaction with surgery, as well as subjective health and energy levels were lower in patients with chronic pouchitis (P < 0.01); however, greater than 80% of these patients would consider undergoing the same procedure again.

Molecular profiling of ulcerative colitis-associated neoplastic progression.

Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.

Reduced Paneth cell alpha-defensins in ileal Crohn's disease.

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human alpha-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC alpha-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC alpha-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of alpha-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of alpha-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Characterization of genotype-phenotype relationships and stratification by the CARD15 variant genotype for inflammatory bowel disease susceptibility loci using multiple short tandem repeat genetic markers.

The classification of ulcerative colitis (UC), Crohn disease (CD), and indeterminate colitis (IC) as forms of inflammatory bowel disease (IBD) is based on clinical, radiological, and histological criteria. The genetic basis of IBD is well founded, and susceptibility loci have been identified on several different chromosomes. We aimed to define genotype-phenotype relationships and interactions with the IBD susceptibility gene CARD15for various IBD susceptibility loci (IBD1, IBD2, IBD5, IBD6, IBD7, and chromosome 4) by characterizing previously described peak LOD score short tandem repeat (STR) markers. The study population consisted of 484 severely affected Caucasian patients with IBD, 144 healthy controls, and 348 nonaffected first-degree relatives of IBD patients. Associations were defined with the use of population- and family-based methodology. Correction for multiple testing was performed with a method based on an experimental false discovery rate. We provide novel evidence to show that IBD2 is involved in susceptibility to IC and terminal ileal CD in this population, with overrepresentation of IBD2 STR D12S83 (GenBank Z16592.1) allele 7 (g.49_60del[CA](6)) in IC (q = 0.038, P = 0.014) and underrepresentation of allele 8 (g.51_60del[CA](5)) in terminal ileal CD (q = 0.038, P = 0.016). The association of IBD2 with IC was confirmed by family-based testing. We also provide novel evidence to show that IBD5 is involved in susceptibility to IC and colonic/ileocolonic CD in this population, with overrepresentation of IBD5 STR D5S1984 (GenBank Z52623.1) allele 5 (g.183_186del[CA](2)) in both IC (q = 0.040, P = 0.005) and colonic/ileocolonic CD (q = 0.040, P = 0.004). Evidence is also given for potential interactions between CARD15and IBD2/IBD5. Other findings include an association of IBD2 with UC, and an association of IBD1 with terminal ileal and colonic/ileocolonic CD.

Afferent limb ulcers predict Crohn's disease in patients with ileal pouch-anal anastomosis.

BACKGROUND & AIMS: Some patients who undergo ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC) or indeterminate colitis are subsequently diagnosed with Crohn's disease (CD). Making the diagnosis of CD in patients with IPAA can be difficult, but it is important for prognostic and therapeutic purposes. The aim of this study was to identify diagnostic features of CD in patients with IPAA. METHODS: We evaluated 87 patients who had undergone IPAA for inflammatory bowel disease. Patients were classified as having UC (n = 28), CD (n = 27), or indeterminate colitis (n = 32) based on review of the original colectomy pathology and the postoperative clinical course. Each patient underwent a pouch endoscopy with biopsies of the pouch and afferent limb. Both the endoscopist and pathologist were blinded to the patient's diagnosis. RESULTS: Afferent limb ulcers (ALUs) were seen on endoscopy in 12 of 27 patients with CD (45%) and 4 of 28 patients with UC (14%) (P = 0.019). After excluding patients who had taken nonsteroidal anti-inflammatory drugs (NSAIDs) within the past month, ALUs were found in 7 of 18 patients with CD (39%) and 0 of 17 patients with UC (P = 0.010). Controlling for NSAID use and smoking, the odds ratio for ALUs indicating CD was 4.67 (P = 0.03). In the UC population, ALUs were seen in 4 of 11 patients (36%) who had taken NSAIDs in the past month and 0 of 17 patients who had not taken NSAIDs (P = 0.016). CONCLUSIONS: ALUs seen on endoscopy are suggestive of CD in patients with inflammatory bowel disease who are not taking NSAIDs.

Interobserver and intraobserver bias exists in the interpretation of anal dysplasia.

INTRODUCTION: Natural history of progression from anal intraepithelial neoplasia to invasive carcinoma remains unproven. The risk of progression may be linked to the severity of dysplasia. Important therapeutic decisions are thus based on the severity of anal intraepithelial neoplasia. Consistency and reliability in the interpretation of anal intraepithelial neoplasia are unproven. METHODS: One hundred ninety anal biopsy specimens were identified for review of dysplasia with a six-point grade system from normal to invasive cancer, evidence of human papillomavirus infection, and quality of histology by three pathologists. RESULTS: Results revealed poor to moderate agreement on grading of quality of histology (weighted kappa score, 0.07-0.22), human papillomavirus status (weighted kappa score, 0.24-0.53), and dysplasia (weighted kappa score, 0.38-0.7). Complete agreement between the original pathology and the three pathologists was observed in only 32 percent of cases. Analysis of 86 slides previously read by one of the pathologists revealed only moderate agreement, with a weighted kappa score of 0.64. CONCLUSION: Significant interobserver and intraobserver bias exists in the interpretation of anal intraepithelial neoplasia. These inconsistencies may explain the uncertainty about the natural progression of anal intraepithelial neoplasia and the varied results of surgery reported for anal intraepithelial neoplasia in the literature.

Characterization and clinical behavior of Crohn's disease initially presenting predominantly as colitis.

PURPOSE: We studied patients with Crohn's disease affecting the colon to characterize disease behavior and to determine whether such patients might be candidates for sphincter-sparing surgery. METHODS: Ninety-two consecutive patients with Crohn's colitis were studied prospectively. Mean follow-up after diagnosis was 82 (range, 6-291) months. Parameters that were evaluated included previous surgery for Crohn's disease, granulomatous vs. nongranulomatous disease, extent of colonic involvement, and presence or absence of extracolonic disease. The clinical course of the disease and postoperative outcome were evaluated. The outcome of Crohn's colitis patients who underwent ileal pouch-anal anastomosis for presumed ulcerative colitis was also evaluated. RESULTS: There were 39 patients with granulomatous colitis and 53 patients without granulomas. There was no statistical difference in the age of diagnosis or presence of small-bowel (23 vs. 27 percent), ileocolic (34 vs. 30 percent), or perineal (36 vs. 22 percent) disease in these patients. At initial presentation, 88 percent of patients with pancolitis had colitis alone without other sites of intestinal disease compared with only 37 percent of patients with segmental colitis (P < 0.001). Kaplan-Meier analysis showed that patients with granulomas and patients with segmental colitis at presentation have a significantly higher recurrence when compared with patients without granulomas and patients with pancolitis (P < 0.03). Thirteen patients without granulomatous disease and eight with granuloma underwent ileal pouch-anal anastomosis. Seven patients (3 with granuloma, 4 without granuloma) had a recurrence of Crohn's disease in the ileal pouch; 2 required pouch removal and permanent diversion for fistulizing disease in the ileal pouch and 5 were successfully treated conservatively without surgery. CONCLUSION: The presence of granulomas and segmental involvement of the colon in patients with Crohn's colitis may reflect a more virulent clinical course. Ileal pouch-anal anastomosis may be considered as an option in select patients with Crohn's colitis without small-bowel or perianal disease. Based on our data, patients with nongranulomatous pancolitis may be better candidates for sphincter-sparing surgery.