Tara M. Connelly

The TNFSF15 Gene Single Nucleotide Polymorphism rs7848647 Is Associated With Surgical Diverticulitis

Objective:To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. Background:A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohns disease (CD), and pouchitis after restorative proctocolectomy. Methods:In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischers exact test. Results:In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk “G” allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. Conclusions:The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making.

Ulcerative Colitis Is Associated With an Increased Risk of Venous Thromboembolism in the Postoperative Period The Results of a Matched Cohort Analysis

OBJECTIVES To determine the rates of venous thromboembolism (VTE) during admission and within 30 days of hospital discharge in inflammatory bowel (IBD) patients undergoing colonic resection using the ACS National Surgical Quality Improvement Project (NSQIP) database and to compare these rates to VTE rates in cohorts of patients undergoing colonic resection for several other colonic pathologies. BACKGROUND High rates of VTE have been demonstrated in hospitalized IBD patients. However, rates of postdischarge VTE in IBD patients are understudied. METHODS Demographic, operative, and outcomes data for 96,999 patients undergoing colonic resection for diverticulitis, colorectal cancer (CRC), benign neoplasms, ulcerative colitis (UC), and Crohns disease (CD) between 2005 and 2011 was obtained. Student t and χ tests were used for univariate analysis. A logistic multivariate analysis was performed with all significant variables. Propensity score matching was utilized to compare the VTE incidences between the groups. RESULTS Highest VTE risk was seen in obese patients [odds ratio (OR) = 1.41], those older than 73 years (OR = 1.58) and with bleeding disorders (OR = 1.44), American Society of Anesthesiology class III/IV (OR = 1.52/1.86), preoperative systemic inflammatory response syndrome (OR = 1.55), sepsis (OR = 1.48) or steroid use (OR = 1.63), and primary diagnosis of UC (OR = 2.10). The UC group had the highest incidence of VTE (2.74%), followed by CRC patients (1.74%). A 1.2% incidence was seen in the CD population, and 41.5% of the UC-VTEs were diagnosed after discharge. CONCLUSIONS This study affirms that inpatient UC patients undergoing colonic resection are at high risk for VTE and suggests that this risk persists into the postdischarge period. Thus, these patients should be given appropriate prophylaxis.

Predictors of recurrence of Crohn's disease after ileocolectomy: a review.

Recurrence after ileocolectomy for Crohns disease (CD) is common and occurs in up to 80% of patients. Such recurrence can result in repeated surgical interventions, an increased need for medical treatment and, frequently, an impaired quality of life. The aim of this overview is to provide a summary of the factors associated with disease recurrence after ileocolectomy for CD. Recurrence can be measured clinically or endoscopically using established scoring systems. Radiology and serologic tests can also be used, oftentimes in conjunction with endoscopy and/or clinical findings. Many patient and operative factors as well as pharmacologic treatments have been studied as potential predictors of recurrence. Of these, only smoking and immunomodulatory or biologic medical treatment have repeatedly been shown to effect recurrence. Genetic predictors have been studied and suggested but further evaluation in larger cohorts is necessary. This paper highlights validated, reproducible scoring systems for recurrence and the key findings of studies including patient demographics, operative techniques, various pharmacological treatments and histological findings as predictors of recurrence post ileocolectomy in CD.

Genetic determinants associated with early age of diagnosis of IBD.

BACKGROUND: Inflammatory bowel disease (IBD) is typically diagnosed at 20 to 40 years of age. However, very young versus elderly patients with IBD may have different mechanisms of disease that may affect prognosis and care. OBJECTIVES: The purpose of this work was to identify single nucleotide polymorphisms associated with age of onset of Crohn’s disease and ulcerative colitis. DESIGN: Patients were genotyped using a custom microarray chip containing 332 IBD-associated single nucleotide polymorphisms. Age at diagnosis as a continuous variable was assessed using linear regression. Patients were then subgrouped by age at diagnosis and compared by the Fisher exact test. Bonferroni correction was used in all of the analyses. SETTINGS: This study was conducted at a tertiary academic hospital. PATIENTS: Sixty patients with Crohn’s disease and 26 with ulcerative colitis were ⩽16 years old, 259 patients with Crohn’s disease and 248 with ulcerative colitis were 17–60 years old, and 10 patients with Crohn’s disease and 20 with ulcerative colitis were >60 years old at diagnosis and included in this study. MAIN OUTCOME MEASURES: Age at diagnosis and single nucleotide polymorphism correlations were measured in this study. RESULTS: The NOD2 single nucleotide polymorphism rs2076756 was associated with younger age at Crohn’s disease diagnosis (p = 0.0002). Patients with the AA/wild-type genotype were diagnosed at 31.9 ± 1.23 years, AG heterozygotes at 25.6 ± 0.99 years, and GG/at-risk allele homozygotes at 22.6 ± 1.32 years. Depending on age categories compared, single nucleotide polymorphisms in POU5F1, TNFSF15, and HLA DRB1*501 were associated with age of Crohn’s disease diagnosis. No genetic associations were seen between ulcerative colitis and linear age at diagnosis; however, the G allele of the LAMB1 single nucleotide polymorphism rs886774 was found to be associated with ulcerative colitis diagnosed at ⩽16 versus >17 years old (p = 0.008). LIMITATIONS: This study was limited to known IBD single nucleotide polymorphisms. CONCLUSIONS: This analysis reaffirms the association between NOD2, a molecule of innate immunity, and early Crohn’s disease onset. This is the first report of a possible association between early Crohn’s disease and the POU5F1, TNFSF15, and HLA DRB1*501 genes. The LAMB1 gene, associated with mucosal basement membrane integrity, was associated with early onset ulcerative colitis and, thus, suggests a fundamentally different mechanism of early disease pathogenesis in ulcerative colitis versus Crohn’s disease.

Ulcerative colitis neoplasia is not associated with common inflammatory bowel disease single-nucleotide polymorphisms

BACKGROUND Neoplasia complicating ulcerative colitis (UC-neoplasia) is a problem that is poorly addressed by present surveillance techniques. The association of greater than 300 single nucleotide polymorphisms (SNPs) with inflammatory bowel disease (IBD) suggests the possibility that certain genetic polymorphisms might identify patients with UC destined for malignant degeneration. This present study tested the hypothesis that presently known IBD-associated SNPs may correlate with UC-neoplasia. MATERIALS AND METHODS A total of 41 patients with UC-neoplasia (mean age 56 ± 2.1 years) were identified from our divisional IBD Biobank (low-grade dysplasia n = 13, high-grade dysplasia n = 8, colorectal cancer [CRC] n = 20). These patients were individually age, sex, and disease duration matched with UC patients without neoplasia. Primary sclerosing cholangitis and family history of CRC were recorded. Patients were genotyped for 314 of the most commonly IBD-associated SNPs by a custom SNP microarray. Logistic regression and Fischer exact test were used for statistical analysis. RESULTS After Bonferroni correction, none of the 314 IBD-associated SNPs correlated with UC-neoplasia when compared with matched UC controls. The incidence of primary sclerosing cholangitis was greater in the UC-neoplasia group (10/41, 24% vs 3/41, 7%; P = .03) compared with UC controls. The severity of neoplasia (low grade dysplasia versus high grade dysplasia versus CRC) correlated with disease duration (7.9 vs 13.4 vs 20.7 years, respectively). CONCLUSION The lack of correlation between well-known IBD-associated SNPs and UC-neoplasia demonstrated in this study suggests that the development of neoplasia in patients with UC is associated with genetic determinants other than those that predispose to inflammation or results from posttranslational modifications or epigenetic factors rather than germline polymorphisms.

Increased Risk of Incisional Hernia after Sigmoid Colectomy for Diverticulitis Compared with Colon Cancer

BACKGROUND We aimed to determine if an increased incidence of incisional hernias is present in patients undergoing sigmoidectomy for diverticulitis vs cancer. The pathophysiology of diverticulitis is poorly understood, but might involve a collagen vascular abnormality that can predispose to incisional hernia. STUDY DESIGN In this IRB-approved, retrospective study, patients who underwent sigmoid colectomies for diverticulitis or cancer between January 2003 and September 2012 were studied. Exclusion criteria included the development of surgical site infections and neoadjuvant chemoradiotherapy. A multivariate logistic regression was used with covariate adjustments for known risk factors for hernia development. RESULTS Four hundred forty-two patients (mean age 59.3 ± 13.9 years) with a median follow-up of 30 months were analyzed. The incidence of incisional hernia was 15.1% in diverticulitis patients vs 5.8% in the cancer cohort (41 of 271 vs 10 of 171; p = 0.003). Univariate analysis of risk factors associated with postoperative incisional hernia included steroid use (p = 0.007), wound packing (p = 0.001), higher American Society of Anesthesiologists classification (p = 0.001), absorbable suture closure (p = 0.02), blood transfusion (p = 0.04), stoma formation (p = 0.02), increased body mass index (p = 0.008), and history of incisional hernia (p = 0.00008). Multivariate logistic regression demonstrated a persistent association between diverticulitis and hernia development (p = 0.01). Odds of a hernia developing after sigmoidectomy for diverticulitis were 2.82 times greater than in the cancer cohort (95% CI, 1.3-6.6). CONCLUSIONS The incidence of an incisional hernia developing after a sigmoid colectomy is significantly higher when performed for diverticulitis as compared with cancer. This might be due to a connective tissue disorder, which predisposes to development of both diverticula and hernias.

The surgical treatment of inflammatory bowel disease-associated dysplasia

Surgical management of colonic dysplasia discovered in the inflammatory bowel disease patient is controversial. Total proctocolectomy (TPC) is the most definitive treatment for the eradication of undiagnosed synchronous dysplasias and/or carcinomas and the prevention of subsequent metachronous lesions in both Crohn’s disease (CD) and ulcerative colitis (UC). However, TPC is not always an attractive option owing to patient comorbidities and patient preference. Historically, dysplasia has been most studied in patients with UC, where the option of reconstruction without a stoma makes TPC more acceptable. Due to a relative lack of research on CD-related dysplasia, surveillance and treatment of CD dysplasia has followed paradigms based on UC data. However, due to pathophysiological differences in CD versus UC, options for surgical management in CD may be more varied than simple TPC, particularly in the less healthy surgical candidate and those who refuse end ileostomy.

The cancer "fear" in IBD patients: is it still REAL?

Increased rates of colorectal cancer (CRC) with high rates of progression from dysplasia to CRC are well documented in the inflammatory bowel disease (IBD) population. This increased risk in the presence of currently improving but still inadequate surveillance techniques confirms that the cancer “fear” in IBD patients is still real. The majority of data on the cancer risk in IBD has been gathered from ulcerative colitis (UC) patients as these patients are generally better studied. Thus surveillance and treatment protocols for Crohn’s disease (CD) are frequently modeled on UC paradigms. Dysplasia in the IBD cohort frequently is a harbinger of local, distant, or metachronous neoplasia. Therefore, frequent surveillance and referral for surgical intervention when dysplasia is detected are justified in both the CD and UC patient.

Volumetric Fat Ratio and Not Body Mass Index Is Predictive of Ileocolectomy Outcomes in Crohn's Disease Patients

Background: Crohns disease (CD) patients are typically underweight; however, a growing cohort of overweight CD patients is emerging. The current study investigates whether body mass index (BMI) or volumetric fat parameters can be used to predict morbidity after ileocolectomy for CD. Methods: One hundred and forty-three CD patients who underwent elective ileocolectomy were identified from our Inflammatory Bowel Disease (IBD) Registry. Patient demographics and operative outcomes were recorded. Visceral (VA) and subcutaneous (SA) adiposity and abdominal circumference (AC) were analyzed on preoperative CT scans using Aquarius iNtuition software. A visceral/subcutaneous ratio (VSR) was calculated. Results: BMI correlated with SA (p = 0.0001), VA (p = 0.0001) and AC (p = 0.0001) but not VSR (p > 0.05). BMI, VA and AC did not predict surgical morbidity (p > 0.05). In multivariate regression analysis, family history of IBD (p = 0.009), high American Society of Anesthesiologists score (p = 0.02) and increased VSR (p = 0.03) were independent predictors of postoperative morbidity. Conclusions: The visceral/subcutaneous fat ratio is a more reliable predictor of postoperative outcomes in CD patients undergoing ileocolectomy than conventional adiposity markers such as BMI. Preoperative calculation of the visceral/subcutaneous fat ratio offers the opportunity to optimize high-risk surgical patients, thus improving outcomes.

A Single Nucleotide Polymorphism in the STAT5 Gene Favors Colonic as Opposed to Small-Bowel Inflammation in Crohn's Disease

BACKGROUND: Crohn’s disease is a chronic inflammatory ailment that can affect the colon and/or small intestine. A genetic basis for disease distribution is being sought, although the available data are seminal. The STAT5 gene is known to influence colonic permeability, mucosal regeneration, and interleukin 2 production, although its role in the distribution of Crohn’s disease is unclear. OBJECTIVE: The aim of this study was identification of single nucleotide polymorphisms associated with Crohn’s distribution, with the goal of distinguishing disease subcategories and differing pathophysiologies. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted in a single tertiary referral center. PATIENTS: A total of 173 patients with Crohn’s disease who were identified from our biobank were segregated by disease distribution (colitis, n = 28; ileocolic disease, n = 116; enteritis, n = 29) and were genotyped for 258 Crohn’s-associated single nucleotide polymorphisms. Patients with ulcerative colitis (n = 119) were also genotyped to confirm the association of identified single nucleotide polymorphisms with small-bowel sparing, colonic pathology. MAIN OUTCOME MEASURES: We investigated an association between single nucleotide polymorphisms and Crohn’s disease distribution. RESULTS: Single nucleotide polymorphism rs16967637 in the STAT5 gene was associated with small-bowel sparing Crohn’s disease when the enteritis group was compared with either a combined colitis/ileocolic group (p = 0.025) or those with only ileocolic disease (p = 0.04). Homozygosity for the at-risk allele (C) was present in 59% of patients with sparing of the small bowel. The association of this single nucleotide polymorphism with small-bowel sparing disease persisted when patients with ulcerative colitis were compared with the group with Crohn’s enteritis (p = 0.036), as well as after combining patients with ulcerative colitis with both the Crohn’s colitis group (p = 0.009) and the Crohn’s ileocolitis/colitis group (p = 0.00008). LIMITATIONS: This study was limited by the small numbers of study subjects with isolated enteritis or colitis. CONCLUSIONS: Single nucleotide polymorphism rs16967637 in the STAT5 gene was the only single nucleotide polymorphism associated with Crohn’s disease without enteritis. Homozygosity for the at-risk allele demonstrated the strongest association with this phenotype. These results suggest a role for this single nucleotide polymorphism in the development of inflammatory bowel disease of the large intestine.