Michelle Vu

Long-term Risk of Acute Diverticulitis Among Patients With Incidental Diverticulosis Found During Colonoscopy

BACKGROUND & AIMS Colonic diverticulosis is the most common finding during routine colonoscopy, and patients often question the significance of these lesions. Guidelines state that these patients have a 10% to 25% lifetime risk of developing acute diverticulitis. However, this value was determined based on limited data, collected before population-based colonoscopy, so the true number of cases of diverticulosis was not known. We measured the long-term risk of acute diverticulitis among patients with confirmed diverticulosis discovered incidentally on colonoscopy. METHODS We performed a retrospective study using administrative and clinical data from the Veterans Affairs Greater Los Angeles Healthcare System, collecting data on patients who underwent colonoscopies from January 1996 through January 2011. We identified patients diagnosed with diverticulosis, determined incidence rates per 1000 patient-years, and analyzed a subgroup of patients with rigorously defined events confirmed by imaging or surgery. We used a Cox proportional hazards model to identify factors associated with the development of diverticulitis. RESULTS We identified 2222 patients with baseline diverticulosis. Over an 11-year follow-up period, 95 patients developed diverticulitis (4.3%; 6 per 1000 patient-years); of these, 23 met the rigorous definition of diverticulitis (1%; 1.5 per 1000 patient-years). The median time-to-event was 7.1 years. Each additional decade of age at time of diagnosis reduced the risk for diverticulitis by 24% (hazard ratio, 0.76; 95% confidence interval, 0.6-0.9). CONCLUSIONS Based on a study of the Veterans Affairs Greater Los Angeles Healthcare System, only about 4% of patients with diverticulosis develop acute diverticulitis, contradicting the common belief that diverticulosis has a high rate of progression. We also found that younger patients have a higher risk of diverticulitis, with risk increasing per year of life. These results can help inform patients with diverticulosis about their risk of developing acute diverticulitis.

Increased Risk for Irritable Bowel Syndrome After Acute Diverticulitis

BACKGROUND & AIMS Individuals with diverticulosis frequently also have irritable bowel syndrome (IBS), but there are no longitudinal data to associate acute diverticulitis with subsequent IBS, functional bowel disorders, or related emotional distress. In patients with postinfectious IBS, gastrointestinal disorders cause long-term symptoms, so we investigated whether diverticulitis might lead to IBS. We compared the incidence of IBS and functional bowel and related affective disorders among patients with diverticulitis. METHODS We performed a retrospective study of patients followed up for an average of 6.3 years at a Veterans Administration medical center. Patients with diverticulitis were identified based on International Classification of Diseases, 9th revision codes, selected for the analysis based on chart review (cases, n = 1102), and matched with patients without diverticulosis (controls, n = 1102). We excluded patients with prior IBS, functional bowel, or mood disorders. We then identified patients who were diagnosed with IBS or functional bowel disorders after the diverticulitis attack, and controls who developed these disorders during the study period. We also collected information on mood disorders, analyzed survival times, and calculated adjusted hazard ratios. RESULTS Cases were 4.7-fold more likely to be diagnosed later with IBS (95% confidence interval [CI], 1.6-14.0; P = .006), 2.4-fold more likely to be diagnosed later with a functional bowel disorder (95% CI, 1.6-3.6; P < .001), and 2.2-fold more likely to develop a mood disorder (CI, 1.4-3.5; P < .001) than controls. CONCLUSIONS Patients with diverticulitis could be at risk for later development of IBS and functional bowel disorders. We propose calling this disorder postdiverticulitis IBS. Diverticulitis appears to predispose patients to long-term gastrointestinal and emotional symptoms after resolution of inflammation; in this way, postdiverticulitis IBS is similar to postinfectious IBS.

Constitutive TL1A Expression under Colitogenic Conditions Modulates the Severity and Location of Gut Mucosal Inflammation and Induces Fibrostenosis

Intestinal fibrostenosis is a hallmark of severe Crohns disease and can lead to multiple surgeries. Patients with certain TNFSF15 variants overexpress TL1A. The aim of this study was to determine the effect of TL1A overexpression on intestinal inflammation and the development of fibrostenosis. We assessed the in vivo consequences of constitutive TL1A expression on gut mucosal inflammation and fibrostenosis using two murine models of chronic colitis. In the dextran sodium sulfate (DSS) and adoptive T-cell transfer models, there was proximal migration of colonic inflammation, worsened patchy intestinal inflammation, and long gross intestinal strictures in Tl1a transgenic compared to wild-type littermates. In the DSS model, myeloid- and T-cell-expressing Tl1a transgenic mice had increased T-cell activation markers and interleukin-17 expression compared to wild-type mice. In the T-cell transfer model, Rag1(-/-) mice receiving Tl1a transgenic T cells had increased interferon-γ expression but reduced T-helper 17 cells and IL-17 production. Narrowed ureters with hydronephrosis were found only in the Tl1a transgenic mice in all chronic colitis models. In human translational studies, Crohns disease patients with higher peripheral TL1A expression also exhibited intestinal fibrostenosis and worsened ileocecal inflammation with relative sparing of rectosigmoid inflammation. These data show that TL1A is an important cytokine that not only modulates the location and severity of mucosal inflammation, but also induces fibrostenosis.

Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor

Background and objectives:Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and methods:Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay.Results:Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.Conclusions:Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

CSA13 inhibits colitis-associated intestinal fibrosis via a formyl peptide receptor like-1 mediated HMG-CoA reductase pathway

Many Crohn’s disease (CD) patients develop intestinal strictures, which are difficult to prevent and treat. Cationic steroid antimicrobial 13 (CSA13) shares cationic nature and antimicrobial function with antimicrobial peptide cathelicidin. As many functions of cathelicidin are mediated through formyl peptide receptor-like 1 (FPRL1), we hypothesize that CSA13 mediates anti-fibrogenic effects via FPRL1. Human intestinal biopsies were used in clinical data analysis. Chronic trinitrobenzene sulfonic acid (TNBS) colitis-associated intestinal fibrosis mouse model with the administration of CSA13 was used. Colonic FPRL1 mRNA expression was positively correlated with the histology scores of inflammatory bowel disease patients. In CD patients, colonic FPRL1 mRNA was positively correlated with intestinal stricture. CSA13 administration ameliorated intestinal fibrosis without influencing intestinal microbiota. Inhibition of FPRL1, but not suppression of intestinal microbiota, reversed these protective effects of CSA13. Metabolomic analysis indicated increased fecal mevalonate levels in the TNBS-treated mice, which were reduced by the CSA13 administration. CSA13 inhibited colonic HMG-CoA reductase activity in an FPRL1-dependent manner. Mevalonate reversed the anti-fibrogenic effect of CSA13. The increased colonic FPRL1 expression is associated with severe mucosal disease activity and intestinal stricture. CSA13 inhibits intestinal fibrosis via FPRL1-dependent modulation of HMG-CoA reductase pathway.

Inflammatory Bowel Disease Associated Colorectal Neoplasia

Patients with ulcerative colitis (UC) or Crohn’s colitis have a greater risk for developing colorectal cancer (CRC). Many studies have described the evolving epidemiology and risk factors for CRC in patients with inflammatory bowel disease (IBD). Recent evidence indicates that the incidence has been decreasing with the advancement of medical and surgical therapies, and surveillance has emerged as the foundation of prevention. Chemoprophylaxis is another area of research; however, given the limited efficacy of these agents, they are only being used in conjunction with endoscopic surveillance. Our ability to formulate effective strategies for the prevention of this dreaded complication expands as more is discovered of the molecular events underlying IBD carcinogenesis. Management strategies are constantly updated as new evidence and endoscopic techniques emerge. In this paper, we review the literature regarding epidemiology, pathogenesis, risk factors and chemoprophylaxis as well as the latest consensus guidelines for management of dysplasia and neoplasia in IBD patients.

Su1182 Intestinal Cathelicidin Levels Predict Prognosis of Ulcerative Colitis Patients

Introduction: Faecal Calprotectin (FC) is a cytosolic protein belonging to the S-100 family of calcium binding proteins found in neutrophils. It is excreted in the intestinal lumen in inflammatory conditions of the gut and can be used to distinguish irritable bowel syndrome (IBS) from other inflammatory bowel conditions such as colitis, diverticulosis, etc. Pointof-contact qualitative FC tests are now available and can be used in primary care to aid decision making for referrals to gastroenterologists for young patients presenting with chronic diarrhoea. Aims: To assess the feasibility and cost effectiveness of a primary care Pathway using a point-of-contact FC Test (Caldetect®) to aid decision making for referrals to gastroenterology in young patients presenting to their primary physicians with chronic diarrhoea. Methods: Primary Care data indicated that approximately 253 referrals are made annually to gastroenterologists from Primary Care to assess patients ,60years presenting with diarrhoea, costing approx. £119,000 for investigations and consultations. Using a Caldetect® (Preventis, GmbH) point of contact FC test, it was estimated that a saving of £89,000 could be achieved. A pathway for investigating chronic diarrhoea using Caldetect® was designed and implemented in the community (population 150,000) between September 2011-March 2012. (this will be presented). FC results were categorised using manufacturer cut-offs of ,15ug/ g, 15-60ug/g and .60ug/g. Patients with FC results of 15-60 and .60 were deemed to have an inflammatory process and referred to Gastroenterology Clinics. Cost analysis was carried out using the 2010-11 tariffs for the NHS. Results: 142 Caldetect® tests were carried out in Primary Care during this pilot phase. Of these, a negative result ( ,15ug/g) was present in 89, with 36 tests being .60ug/g. 3 tests were at the intermediate level and 14 tests could not be accurately reported. Negative results were managed in primary care as IBS. A monthly cost savings of £6100 was calculated taking consultation and endoscopy tariffs into account. Conclusion: This pilot study demonstrates the feasibility and cost effectiveness of a Pathway for decision making and a point-of-care faecal calprotectin test in rationalising referrals to Gastroenterologists for chronic diarrhoea.

Mo1030 Less Experienced Endoscopists are More Likely to Report “Sub-Optimal” Bowel Preparation Quality vs. More Experienced Endoscopists

Less Experienced Endoscopists are More Likely to Report “Sub-Optimal” Bowel Preparation Quality vs. More Experienced Endoscopists Hank S. Wang, Scott Kubomoto, Aaron Lee, Luis H. Ocampo, Michael D. Baek, Gobind N. Sharma, Jessica Liu, Rusha Modi, Nattapaun N. Thepyasuwan, Alexander Levy, Michelle Vu, Victoria Sheen, Mary A. Atia, Kamyar Shahedi, Bradley J. Snyder, Poyrung Poysophon, Brennan M. Spiegel

Tu1907 Gene-Smoking Interactions in Inflammatory Bowel Disease

Background: Genome-wide association studies (GWAS) have been pivotal to increasing our understanding of intestinal disease. However, the mode by which genetic variation results in phenotypic change remains largely unknown, with many associated polymorphisms likely to modulate gene expression. Analyses of expression quantitative trait loci (eQTL) to date indicate that as many as 50% of these are tissue specific. Here we report a comprehensive eQTL scan of intestinal tissue. Methods: Patients who had undergone ileal pouch anal anastomosis and closure of ileostomy at least one year prior to recruitment were prospectively enrolled at Mount Sinai Hospital in Toronto. Ileal tissue biopsies predominantly normal on endoscopy and histology from the afferent limb of these individuals were obtained and preserved in RNAlater. Total RNA was extracted with the QIAGEN miRNeasy Kit and mRNA analysis was performed on Affymetrix Human Gene 1.0 ST arrays. DNA was obtained from whole-blood samples from the same individuals and genotyped using the Illumina Human OmniExpress platform. Preliminary cis-eQTL analysis (±50Kb around each gene) was carried out on 169 subjects encompassing the expression levels of 19,047 unique autosomal genes listed in the NCBI database and 565,802 dbSNPs (Call Rate ≥ 95%; MAF ≥ 5%; HardyWeinberg χ2 ≤ 6.635). The Kruskal-Wallis test was used to compare expression values across different genotypes and Bonferroni correction for multiple testing was applied at an alpha level of 5%. Results: The presence of 3,074 statistically significant cis-eQTLs associated with 575 genes was detected with this analysis. eQTLs associated with the same expression trait were in high linkage disequilibrium. 230 (40%) of these 575 genes have been reported as quantitative traits in liver tissue by a prior study using similar methodology. After false discovery rate correction for multiple testing, our analysis confirmed previously published cis-eQTLs that are also IBD associated SNPs: rs2298428/UBE2L3, rs1050152/SLC22A4 and rs2631372/SLC22A5. Conversely, the majority of significant cis-eQTLs are novel and possibly tissue specific. These pertain to many aspects of cellular function from division to antigen processing and presentation. Conclusion: eQTL analysis of intestinal tissue substantiates reports in the literature that some eQTLs remain stable across cell types while many others are specific to the sampled location. Our findings not only confirm, but also significantly expand the number of known genotypes associated with expression and could help elucidate the mechanisms of intestinal disease.