1007fs, G908R, R702W Mutations and P268S, IVS8+158 Polymorphisms of the CARD15 Gene in Turkish Inflammatory Bowel Disease Patients and Their Relationship with Disease-Related Surgery

Introduction CARD15 gene mutations may present different frequencies in populations and sometimes surgical interventions may become a necessary therapy for inflammatory bowel disease patients. Mutations of 1007fs, G908R, R702W and polymorphisms of P268S, IVS8⁺¹⁵⁸ of the CARD15 gene and their relation with disease-related surgery were investigated in Turkish inflammatory bowel disease patients in this study. Material and Method 1007fs, G908R, R702W mutations and P268S, IVS8⁺¹⁵⁸ polymorphisms of CARD15 gene were analyzed in 130 inflammatory bowel disease patients (67 Crohn’s disease, 63 ulcerative colitis) and 87 healthy controls. After obtaining DNA samples, genotyping was performed by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) analysis. Results were evaluated by statistical analysis and accepted as significant if P < 0.05. Results R702W gene mutation was significantly lower in the inflammatory bowel disease group (1.5%) than the controls (4.8%) (P < 0.05). The overall allele frequency of mutations in the inflammatory bowel disease group (2.7%) was lower than in controls (6.6%) (P < 0.05). Disease-related surgery history was present in 20 Crohn’s and 25 ulcerative colitis patients; familial history was present in four Crohn’s and five ulcerative colitis patients. Statistically, no relationship was detected between disease-related surgeries and the investigated genetic tests. Conclusion In Turkish patients, no important relationship was detected between the investigated allele frequencies of the CARD15 gene and inflammatory bowel disease nor between disease-related surgeries and inflammatory bowel disease. Dedicated to the memory of the Turkish scientist Turgut Tukel MD. Thanks for his contributions and supports.     

Is Indeterminate Colitis Determinable?

About 10% of patients with colitis due to inflammatory bowel disease have indeterminate colitis. Despite newer diagnostic tools, the frequency has not diminished over the past 33 years. The current preferred term among academicians is colonic inflammatory bowel disease unclassified (IBDU), although indeterminate colitis is the term endorsed for inclusion in the ICD-10 coding system. Indeterminate colitis is more frequent among children. The anti-Saccharomyces cerevisiae (ASCA) and perinuclear anti-cytoplasmic antibody (pANCA) are useful in distinguishing IBDU from ulcerative colitis and Crohn’s disease. However, current serologic and genetic studies, as well as endoscopic and imaging studies lack sufficient positive predictive values to make a definite diagnosis of Crohn’s colitis or ulcerative colitis. Patients with IBDU who undergo proctocolectomy with ileal pouch-anal anastomosis have more complications than patients with ulcerative colitis. Although some patients with indeterminate colitis eventually develop characteristic ulcerative colitis or Crohn’s disease, a subgroup are durably indeterminate.     

Differences in Yeast Intolerance Between Patients with Crohn’s Disease and Ulcerative Colitis

Purpose Alimentary factors, especially those modifying the intestinal flora, may influence the course of inflammatory bowel disease. It is known that T and B cells of patients with Crohn’s disease can be stimulated with the yeast antigen, mannan. We evaluated the impact of eating habits with special respect to food containing yeast on the course of inflammatory bowel disease. Methods Questionnaires were sent to 180 German-speaking patients of the Inflammatory Bowel Disease Outpatient Clinic at the University Hospital Bern, Switzerland. The following information was obtained by the questionnaires: (1) course of disease, (2) eating habits, (3) environmental data, and (4) inflammatory bowel disease questionnaire. The survey was anonymous. Results A total of 145 patients (80.5 percent 95 with Crohn’s disease, and 50 with ulcerative colitis) responded. Food items containing yeast were better tolerated by patients with ulcerative colitis than by patients with Crohn’s disease. A significant difference between the two groups was observed concerning food containing raw yeast (dough, P = 0.04; and pastry, P = 0.001). Conclusions Food items containing raw yeast led to more frequent problems for patients with Crohn’s disease than for patients with ulcerative colitis. This observation supports our previous data, which showed the stimulatory effect of the yeast antigen, mannan, on B and T cells of patients with Crohn’s disease but not of controls. Poster presentation at Digestive Disease Week (DDW), organized by the American Gastrointestinal Association, Chicago, Illinois, May 14 to 19, 2005.     

Optical Coherence Tomography in Inflammatory Bowel Disease: Prospective Evaluation of 35 Patients

Purpose  Optical coherence tomography is a technique using infrared light in tissues of the gastrointestinal tract and human colon affected by inflammatory diseases. We evaluated whether there are specific patterns of optical coherence tomography for inflammatory bowel disease and compared the technique performance to the histology. Methods  Optical coherence tomography was performed in 35 patients (18 men; 31 ulcerative colitis, 4 Crohn’s disease). The images were obtained from affected and normal colon at endoscopy. Two biopsies of the sites visualized were taken. Two endoscopists scored the images, and two pathologists, blind to the endoscopy and optical coherence tomography, performed the histologic evaluation. Results  Three optical coherence tomography patterns were identified: 1) mucosal backscattering alteration, 2) delimited dark areas, and 3) layered colonic wall. Compared with the histology, mucosal backscattering alteration was the most effective in recognizing the disease in patients (P = 0.007 in colon segments affected, and P < 0.001 in normal segments). The sensitivity and specificity have been 100 and 78 percent, respectively. Conclusions  The in vivo optical coherence tomography correctly detected inflammatory bowel disease features in affected and apparently normal colon, and allowed to discriminate patterns for active ulcerative colitis and Crohn’s disease.     

Emu Oil Increases Colonic Crypt Depth in a Rat Model of Ulcerative Colitis

Background  

Current treatments for the inflammatory bowel diseases, encompassing Crohn’s disease and ulcerative colitis, are variably effective. Emu oil, extracted from emu fat, predominantly comprises fatty acids, with purported claims of anti-inflammatory properties.     

Dopamine D2 Receptor Polymorphisms in Inflammatory Bowel Disease and the Refractory Response to Treatment

Dopamine and its receptors may be involved in inflammatory reaction. The availability of this molecule depends on its receptors. The DRD2 gene, which codifies for the D2 dopamine receptor, has several polymorphisms. In this study, the DRD2 TaqIA polymorphism, which confers a decreased receptor density, was evaluated in 313 individuals including 220 inflammatory bowel disease patients (143 patients with Crohn’s disease and 77 with ulcerative colitis) and in 93 healthy blood donors. The analysis was carried out by PCR-RFLP techniques. The frequencies of A ₁ A ₁ and A ₂ A ₂ genotypes were similar among Crohn’s disease, ulcerative colitis patients, and health controls. Also, the genotype frequency was similar in different groups of disease localization, behavior, and age of disease onset. However, the Crohn’s disease patients carriers of A ₂ A ₂ genotype showed a lower risk for development refractory Crohn’s disease (37 out 65) than A ₁ A ₁ and A ₁ A ₂ carriers (28 out of 65) [(OR=0.4, 95% CI 0.21–0.87; p=0.02)]. Our results support an involvement of the dopamine receptor in inflammatory bowel disease and suggest a new potential target for therapy in refractory Crohn’s disease patients.     

Diagnostic methodologies: serology, endoscopy, and radiology

The two major inflammatory bowel diseases, Crohn’s disease (CD) and ulcerative colitis (UC), represent clinicopathologic entities that traditionally have been diagnosed on the basis of a combination of clinical, radiologic, endoscopic, and histologic features. Serum perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have recently been added to our diagnostic armamentarium. Several studies have demonstrated that UC-associated pANCAs recognize nuclear antigens. Additional studies have demonstrated that the pANCA human monoclonal antibody (mAb) Fab 5–3 reacts with histone H1 and with bacterial and mycobacterial antigens. Several reports have suggested that, in CD, pANCA and ASCA are correlated with colonic and small bowel disease respectively. One study found that higher ASCA levels were correlated with more aggressive CD. Serology may prove to be useful in predicting the evolution of indeterminate colitis. Magnetic resonance imaging (MRI) and leukocyte scintigraphy hold promise in identifying inflammatory CD. MRI enteroclysis is useful in identifying both luminal small bowel disease and extraluminal complications. A recent study of surveillance colonoscopy in extensive Crohn’s colitis showed a high risk of dysplasia and cancer.     

Incidence and Risk of Intestinal and Extra-intestinal Complications in Medicaid Patients with Inflammatory Bowel Disease: A 5-Year Population-Based Study

Background and Aim  

Intestinal and extra-intestinal complications are associated with inflammatory bowel disease (IBD) but their exact incidence is not well known. In order to improve our understanding of their incidence and impact, we assessed the complications associated with ulcerative colitis (UC) and Crohn’s disease (CD) in a population-based study in Medicaid patients.     

Age and Indication for Referral to Capsule Endoscopy Significantly Affect Small Bowel Transit Times: The Given Database

The purpose of this study was to examine the effect of age and selected indications for capsule endoscopy on small bowel transit times. Data on 67 clinical studies (790 subjects with different gastrointestinal pathologies [49.5% males; mean age, 51.9 ± 18.33 years; range, 18–91 years] and 87 healthy volunteers) were retrieved from the company (Given Imaging, Ltd.)-sponsored database. All subjects swallowed the PillCam SB Capsule after a 12-hr fast. The capsule reached the cecum in all 877 participants. Indications for referral for capsule endoscopy were as follows: 372 obscure gastrointestinal bleeding, 96 suspected Crohn’s disease, 65 celiac disease, 54 irritable bowel syndrome, and 116 familial adenomatous polyposis, intestinal lymphoma, or ulcerative colitis. One group consisted of patients <40 years old (n = 235), and the other patients 40 years old (n = 555). The younger group, volunteers, and Crohn’s disease patients had significantly shorter small bowel transit times than the others (P < 0.001). Gastric emptying indirectly influenced capsule transit time.     

Current and future anti-TNF therapy for inflammatory bowel disease

Opinion statement Anti-tumor necrosis factor-α (anti-TNF) therapy has become a very important modality in the treatment of patients with inflammatory bowel disease. A number of anti-TNF medications have been investigated for this purpose, many via randomized controlled trials. Infliximab, the most studied of these agents, has shown impressive efficacy in the treatment of luminal and fistulizing Crohn’s disease, as well as ulcerative colitis. Adalimumab and certolizumab have shown similar efficacy in Crohn’s disease but have not yet been studied in ulcerative colitis. Less impressive results were seen in randomized controlled trials involving CDP-571, etanercept, or onercept for patients with Crohn’s disease. Thalidomide and CNI-1493 have been evaluated only preliminarily in small, open-label pilot studies in patients with Crohn’s disease. The future of anti-TNF therapy in inflammatory bowel disease is very bright, as exciting new developments continue to be made at a rapid pace.     

The Role of N-Acetyltransferase 2 Polymorphism in the Etiopathogenesis of Inflammatory Bowel Disease

Background and Purpose  

Inflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn’s disease (CD), which are complex genetic disorders resulting from the interplay between several genetic and environmental risk factors. The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalyzed by NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. The aim of our study was to determine whether there is any association between the susceptibility to inflammatory bowel disease among the variations of NAT2 genotypes.     

The role of laparoscopic surgery for ulcerative colitis: systematic review with meta-analysis

Purpose  

Crohn’s disease is established in laparoscopic surgery due to partial bowel dissection and low postoperative complication rate. However, laparoscopic surgery for ulcerative colitis remains further discussed even if the trend of minimally invasive technique exists. This study is to figure out how laparoscopic surgery works for ulcerative colitis.     

The Role of Tacrolimus in Inflammatory Bowel Disease: A Systematic Review

Therapeutic management of inflammatory bowel disease remains beyond the limits of conventional therapy in many cases. Novel therapies used include tacrolimus, a new powerful immunosuppressive drug, employed in some case reports and a few studies that have tried to evaluate its effectiveness in Crohn’s disease and ulcerative colitis with promising results, but its role in the management of inflammatory bowel disease remains controversial. We performed a systematic review that analyzed a total of 23 reported experiences in 286 patients with inflammatory bowel disease treated with tacrolimus. Although most of the published studies are uncontrolled, short, and heterogeneous, promising results have been obtained in fistulizing disease, unresponsive cases of both ulcerative colitis and Crohn’s disease, and even extraintestinal manifestations. The overall outcome was good enough to consider tacrolimus as a rationale therapeutic option. However, comparative studies with standard therapeutic options like infliximab are needed to assess the correct role that tacrolimus may play in these patients.     

Hospitalizations for Inflammatory Bowel Disease Among US Military Veterans 1975–2006

Background The Department of Veterans Affairs (VA) is the largest healthcare system in the United States. The VA database was used to analyze patterns of hospitalization for inflammatory bowel disease (IBD) among US military veterans. Methods The study used the VA Patient Treatment File (PTF) between 1975 and 2006. Each hospital record extracted from the PTF included diagnosis, patient age, and ethnicity. Patient age was analyzed in three age groups: 0–44, 45–64, and 65+. Patient ethnicity was analyzed by two broad categories as white and nonwhite. Results Among veterans, Crohn’s disease was more common than ulcerative colitis and both diseases were more common in whites than in nonwhites. During the past 30 years, the age distributions of both diseases have shifted towards older patients who have come to represent an increasingly larger fraction of patients with Crohn’s disease, as well as ulcerative colitis. Hospitalization rates for inflammatory bowel disease among whites recently declined, while most rates among nonwhites continued to rise throughout the observation period. Conclusion The present study revealed a time-dependent shift towards older ages in the age distribution of IBD among hospitalized veterans. These changes, which have been observed similarly in other US statistics, may reflect a birth-cohort phenomenon underlying the long-term time trends of IBD.     

Serum lysozyme,serum proteins,and immunoglobulin determinations in nonspecific inflammatory bowel disease

The serum levels of lysozyme, serum electrophoresis, and serum immunoglobulins were determined prospectively in 101 patients with ulcerative colitis, ulcerative proctitis, Crohn's disease, or nonclassifiable nonspecific inflammatory bowel disease. Although the mean serum lysozyme concentration of patients with Crohn's disease (10.5±6.8 μg/ml) and ulcerative colitis (9.6±4.1 μg/ml) performed by a standardized lysoplate method was significantly greater than normal controls (6.0±1.5 μg/ml), the results did not correlate with the diagnosis nor with the degree of disease activity. Individually separated protein fractions and serum immunoglobulins also did not correlate with the serum lysozyme levels. This study indicates that measurement of the level of serum lysozyme in individual patients is not helpful in determining the cause or degree of activity of non-specific inflammatory bowel disease.     

Enhanced Intestinal Expression of the Proteasome Subunit Low Molecular Mass Polypeptide 2 in Patients with Inflammatory Bowel Disease

Purpose Low molecular mass polypeptide 2 is an inducible immunoproteasome subunit. The expression of low molecular mass polypeptide 2 has not been examined in the intestine of patients with inflammatory bowel disease. This study was designed to determine whether the intestinal expression of low molecular mass polypeptide 2 was enhanced in a group of patients with inflammatory bowel disease compared with a group of control patients without inflammatory bowel disease. Moreover, we examined the association between low molecular mass polypeptide 2 expression and histologic pathology in these patients. Methods Twenty-one patients participated in the study. These included six control subjects without inflammatory bowel disease, eight patients with ulcerative colitis, and seven patients with Crohn’s disease. Intestinal low molecular mass polypeptide 2 expression was evaluated by immunohistochemistry, as well as by Western blot. Histology scores (0–40 severity scale) were determined on the same sections of intestine as those used for low molecular mass polypeptide 2 histochemistry. Results By immunohistochemistry, low molecular mass polypeptide 2 expression was significantly enhanced (P < 0.05 vs. control subjects) throughout visibly diseased areas of colon, rectum, and ileum from patients with inflammatory bowel disease. Low molecular mass polypeptide 2 expression also was increased in macroscopically normal intestine from patients with inflammatory bowel disease compared with normal tissue from control subjects. There was a significant correlation (P < 0.0001) between low molecular mass polypeptide 2 expression and histologic pathology in our patients. Western blot results confirmed that low molecular mass polypeptide 2 expression was enhanced in patients with ulcerative colitis (3.1-fold) and in patients with Crohn’s disease (3.5-fold). Conclusions Intestinal low molecular mass polypeptide 2 expression is significantly increased in inflammatory bowel disease. The association between intestinal low molecular mass polypeptide 2 expression and histologic pathology suggests that this proteasome subunit plays a role in the pathogenesis of inflammatory bowel disease. Supported by a grant from Philadelphia Health Care Trust, Philadelphia, Pennsylvania. Presented at the Digestive Disease Week meeting, Los Angeles, California, May 21 to 24, 2006.     

The prevalence of ocular involvement in patients with inflammatory bowel disease

Purpose The aim of this prospective randomized clinical study was to evaluate the prevalence of ocular involvement in patients with inflammatory bowel disease (IBD). Materials and methods We prospectively evaluated 116 patients who went to the gastroenterology clinic with endoscopically proven IBD between December 2001 and February 2005. All patients were examined for evidence of ocular manifestations of IBD. Twenty patients had Crohn’s disease and 96 had ulcerative colitis. The examination consisted of slit-lamp examinations, tonometry, visual acuity, and indirect ophthalmoscopy. Results The mean age of the 116 patients with IBD who were enrolled was 40.6 ± 14.4 years (range 16 to 75). Twelve of 20 patients (60%) with Crohn’s disease and 22 of 96 patients (22.92%) with ulcerative colitis had ocular involvement. The most common ocular findings were conjunctivitis (8.62%) and blepharitis (6.9%) followed by uveitis (5.17%), cataract (5.17%), and episcleritis (3.45%). Extraintestinal complications were seen in 12 (35.3%) of 34 patients with ocular involvement and in 16 (19.5%) of 82 patients without ocular involvement. Conclusion Because the ocular complaints of IBD patients are often nonspecific, it may be helpful to performed eye examinations as a routine component in the follow-up of these patients. It is well-known that early diagnosis and treatment of ocular involvement may prevent serious ocular complications that could be associated with significant visual morbidity. In addition, clinicians should be aware that some ocular diseases, such as uveitis and scleritis, might precede a diagnosis of ulcerative colitis or Crohn’s disease.     

The Effect of Crohn’s Disease on Outcomes After Restorative Proctocolectomy

Purpose This study was designed to compare postoperative adverse events and functional outcomes after ileal pouch-anal anastomosis between patients with Crohn’s disease and those with non-Crohn’s disease diagnoses. Methods A literature search was performed to identify studies published between 1980 and 2005 comparing outcomes of patients undergoing ileal pouch-anal anastomosis for Crohn’s disease, ulcerative colitis, and indeterminate colitis. Random-effect, meta-analytical techniques were used and sensitivity analysis was performed. Results Ten studies comprising 3,103 patients (Crohn’s disease=225; ulcerative colitis=2,711; indeterminate colitis=167) were included. Patients with Crohn’s disease developed more anastomotic strictures than non-Crohn’s disease diagnoses (odds ratio, 2.12; P=0.05) and experienced pouch failure more frequently than patients with ulcerative colitis (Crohn’s disease vs. ulcerative colitis: 32 vs. 4.8 percent, P<0.001; Crohn’s disease vs. indeterminate colitis: 38 vs. 5 percent, P<0.001). Urgency was more common in Crohn’s disease compared with non-Crohn’s disease: 19 vs. 11 percent (P=0.02). Incontinence occurred more frequently in Crohn’s disease compared with non-Crohn’s disease patients: 19 vs. 10 percent (odds ratio, 2.4; P=0.01). Twenty-four-hour stool frequency did not differ significantly between Crohn’s disease, ulcerative colitis, or indeterminate colitis. Patients with isolated colonic Crohn’s disease were not significantly at increased risk of postoperative complications or pouch failure (P=0.06). Conclusions Patients with Crohn’s disease undergoing ileal pouch-anal anastomosis should be appropriately counseled toward poorer functional outcomes and higher failure compared with non-Crohn’s disease patients. It maybe possible to preoperatively select patients with isolated colonic Crohn’s disease who may benefit from ileal pouch-anal anastomosis with acceptable adverse outcomes. Presented at the meeting of the European Society of Coloproctology, Lisbon, Portugal, September 13 to 16, 2006.     

Prevalence of Macrocreatinkinase Type 1 in Patients with Inflammatory Bowel Disease

Macro-creatine-kinases are isoenzymes of creatinine-kinases (CK). They have been classified in two types: type 1 (CK bound to an immunoglobulin) and type 2 (an oligomeric mitochondrial CK). CK type 1 has been found in patients with ulcerative colitis (UC) but not in Crohn’s disease (CD). However, there are no studies evaluating macro-creatinkinase prevalence in inflammatory bowel disease (IBD). We included 159 consecutive patients (72 UC, 85 CD; 2 indeterminate colitis). Creatin-kinase total activity and isoenzymes activities were determined. Twelve (16.7%) patients with UC and one of the two patients with indeterminate colitis had serum macro-creatinkinase type 1 while no CD patients displayed this macromolecule (P < 0,001). Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratio were calculated for ulcerative colitis versus Crohn’s disease diagnosis, being 16.7, 98.9, 92.3, 59, 14.5, and 0.84% respectively. There was no correlation with age, gender, time from diagnosis, associated diseases, concomitant medication or disease activity. In conclusion our data suggests that the presence of macro-CK in IBD favors the diagnosis of ulcerative colitis. Further studies are necessary to understand the significance of this finding in a subset of patients with IBD.