Maria O'Sullivan

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

NOD2/caspase recruitment domain (CARD)15 variants are identified in up to 50% of Crohns disease (CD) patients. Functional variants of toll-like receptor-4 (TLR4) and CD14 genes may also be relevant to disease pathophysiology. We aimed to assess the contribution of NOD2/CARD15, TLR4 and CD14 variants in Scottish and Irish CD patients. In all, 612 patients with well-characterised inflammatory bowel disease (252 Scottish CD, 247 Scottish UC, 113 Irish CD) and 304 controls were genotyped for variants of NOD2/CARD15 (1007fsinsC, G908R, R702W, P268S), TLR4 (A299G) and CD14 (T-159C). Genotype–phenotype analyses were performed. Variant 1007fsinsC (P=0.003) and G908R (P=0.008) but not R702W (P=0.269) alleles were more prevalent in Scottish CD (4.7, 1.8 and 7.1%, respectively) than Scottish control (2.3, 0.3 and 5.4%). CD allelic frequencies were lower than the series from Europe (P<0.00001) and North America (P<0.00001) but not Scandinavia (P<0.7). Associations were identified with age at diagnosis (P=0.002), ileal disease (P<0.02), penetrating disease (P=0.04) and inflammatory joint disease (P<0.02). TLR4 and CD14 variants did not differ between CD and controls. In conclusion, we present compelling evidence for genetic heterogeneity within Europe. These NOD2/CARD15 variants have a minor contribution in Scottish and Irish CD patients, consistent with an emerging pattern from Northern Europe.

Patient knowledge and educational needs in irritable bowel syndrome.

Objective Educating patients with irritable bowel syndrome (IBS) about their disorder may promote a strong physician ‐ patient interaction, is a recommended approach for treating mild IBS and may reduce healthcare use. Our aim was to identify the information needs, levels and associated factors in IBS, and to contrast this with patients with inflammatory bowel disease (IBD). Design Seventy adult IBS patients (Rome criteria) were prospectively recruited, together with 82 ulcerative colitis (UC) and 60 Crohns disease (CD) patients. Demographic data, clinical data, and anxiety and depression scores (HAD scale) were recorded. Patients rated their perceived levels of disease knowledge and satisfaction with their knowledge level on visual analogue scales. Qualitative data on disease information needs were obtained by an open‐ended question. Setting Gastroenterology out‐patient clinic. Results The majority of IBS patients (77%; n = 54) and over half of IBD patients (56%; n = 79) required further information about their disease. The primary issues for IBS patients were bowel cancer risk and diet. Queries about medications ranked top for UC, while prognosis and cancer risk jointly ranked top for CD. In the IBS group, 27% rated their knowledge as < 25 out of 100 compared to 10% of IBD patients. The perceived level of knowledge in IBS was significantly negatively associated with length of hospital consulting (rs = −0.32; P = 0.04). Conclusion Most IBS patients feel insufficiently informed, particularly in relation to risk of serious disease and role of diet. Educating IBS patients about their disorder may play a role in reducing healthcare use. Eur J Gastroenterol Hepatol 12:39‐43

High prevalence of overweight and obesity in adults with Crohn's disease: Associations with disease and lifestyle factors

BACKGROUND AND AIMS Obesity and overweight are major public health issues. Although traditionally associated with weight loss, there is now evidence that increasing Body Mass Index (BMI) and overweight are emerging features of Crohns disease (CD) and may be associated with more severe disease course. The aim of the study was to determine the prevalence of overweight and obesity in patients with CD compared with matched healthy controls and to identify disease-specific and generic factors associated with current BMI in this group. METHODS This was a prospective case-control study (n=200), comprising 100 CD outpatients and 100 age-, sex- and socioeconomically-matched healthy controls. BMI, Crohns disease activity index (CDAI), clinical and lifestyle factors and circulating inflammatory markers were assessed. RESULTS Overall, 40% of patients with CD were overweight/obese (BMI ≥ 25 kg/m(2)) compared with 52% of controls (P = 0.206). On regression analysis, higher current BMI was significantly associated with disease specific factors, namely lower disease activity (CDAI) and lower white cell count, suggesting stable disease, as well as older age and lower physical activity. BMI was not significantly associated with the need for surgery or the need for corticosteroids. We identified a novel association between higher BMI and higher CRP, a marker linked both with obesity in the general population and with CD. CONCLUSIONS Overweight was common in out-patients with CD and appeared to reflect current wellness, older age and sedentary lifestyles. The potential long-term implications of high BMI for CRP and inflammatory load merit further study.

Vitamin D deficiency in Crohn's disease: prevalence, risk factors and supplement use in an outpatient setting.

BACKGROUND AND AIMS Vitamin D deficiency impacts on bone health and has potential new roles in inflammation. We aimed to determine the prevalence of and risk factors for vitamin D deficiency and to explore vitamin D supplement usage in patients with Crohns disease (CD) in an outpatient setting, compared with controls. METHODS Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured by radioimmunoassay in 151 participants, comprising 81 CD patients and 70 age-, sex- and socio-economic status-matched healthy controls. Levels of 25(OH)D <50 nmol/L were classed as deficient. Data on vitamin supplement usage were recorded for all participants at interview. RESULTS Vitamin D deficiency was common in patients with CD (63%) and significantly higher in winter than summer (68% v 50%; p<0.001, χ(2)). Notably, the deficiency rate remained high even in summer (50%). On regression analysis, 25(OH)D levels were inversely associated with winter season. Disease-specific factors for lower serum 25(OH)D levels were longer disease duration and smoking. Overall, 43% of patients reported using a vitamin D-containing supplement, primarily at low dosages (200-400 IU/d); however, this level of supplement did not prevent deficiency. For the majority of CD patients, 25(OH)D remained below optimal levels proposed to confer bone and immune health benefits. CONCLUSIONS Vitamin D deficiency was common in patients with CD and associated with longstanding disease, smoking and winter. While over 40% of patients used a vitamin D-containing supplement, the dosages were inadequate to prevent deficiency. Appropriate vitamin D screening and supplementation should be considered in the context of health promotion of outpatients with CD.

Mast cell tryptase reduces junctional adhesion molecule-A (JAM-A) expression in intestinal epithelial cells: implications for the mechanisms of barrier dysfunction in irritable bowel syndrome.

OBJECTIVES:The objective of this study was to investigate how mast cell tryptase may influence intestinal permeability and tight junction (TJ) proteins in vitro and explore translation to irritable bowel syndrome (IBS).METHODS:We investigated the effect of: (1) tryptase on Caco-2 monolayers, (2) mast cell degranulation in a Caco-2/human mast cell-1 (HMC-1) co-culture model, (3) mast cell degranulation±tryptase inhibition with nafamostat mesilate (NM). Epithelial integrity was assessed by transepithelial resistance (TER), permeability to fluorescein isothiocyanate (FITC)-dextran and transmission electron microscopy (TEM). The expression of junctional proteins zonula occludens-1 (ZO-1), junctional adhesion molecule-A (JAM-A), claudin-1 (CLD-1), CLD-2, CLD-3, occludin and E-cadherin was determined by western blot analysis and immunofluorescence confocal microscopy. Based on the in vitro results, we further assessed JAM-A expression in biopsy tissue (cecum) from 34 IBS patients, 12 controls, and 8 inflammatory controls using immunofluorescence confocal microscopy and explored associations between JAM-A and IBS symptoms.RESULTS:ptase disrupted epithelial integrity in Caco-2 monolayers as shown by a significant decrease in TER, an increase in permeability to FITC-dextran, and a decrease in the expression of junctional proteins JAM-A, CLD-1, and ZO-1 within 24 h. Correspondingly, in the Caco-2/HMC-1 co-culture model we showed a significant decrease in TER, an increase in permeability to FITC-dextran, and the presence of open TJs (TEM) in response to mast cell degranulation within 24 h. In this co-culture model, mast cell degranulation significantly decreased JAM-A and CLD-1 protein expression at 24 h. Tryptase inhibition (NM) significantly reduced the effect of mast cell degranulation on the junctional protein JAM-A, TER, and FITC-dextran flux. In IBS, epithelial JAM-A protein expression was significantly reduced in IBS tissue compared with controls. Lower JAM-A expression was associated with more severe abdominal pain (rs=−0.69, P=0.018) and longer duration of symptoms (rs=−0.7, P=0.012) in IBS-alternating subtype.CONCLUSIONS:uced JAM-A expression in vitro appears to contribute to the underlying mechanisms of altered epithelial integrity in response to tryptase released from degranulating mast cells. In IBS, JAM-A expression was significantly reduced in the cecal epithelium and associated with abdominal pain severity. JAM-A may provide new insights into the underlying mechanisms in IBS.

Patients with chronic pancreatitis are at increased risk for osteoporosis.

Objectives Patients with chronic pancreatitis may be at an increased risk of low bone density because of malabsorption of vitamin D and calcium, poor diet, pain, alcoholism, and smoking. We investigated the rates of osteoporosis in patients with chronic pancreatitis compared to matched controls. Methods The study was cross sectional in design. Sixty-two patients (mean age, 47.9 years; 72.6% male) and 66 matched controls were recruited. Dual-energy x-ray absorptiometry, smoking, and socioeconomic data were recorded. Results Thirty-four percent of patients had osteoporosis compared to 10.2% of controls. T-scores at the right femoral neck were lower in patients than controls (P = 0.005). Patients in the highest smoking tertile had the poorest T-scores at the lumbar vertebrae and total hip. Patients in the youngest age tertile had the highest T-scores (P = 0.003), but there was no sex difference. Conclusions Patient osteoporosis rates were triple that of controls, and almost 7 times what has been previously reported. Given the resource burden of osteoporosis, we suggest that routine bone density assessment is performed in patients with chronic pancreatitis.

Nutrition Treatment of Deficiency and Malnutrition in Chronic Pancreatitis A Review

Chronic pancreatitis results in exocrine and endocrine dysfunction, affecting normal digestion and absorption of nutrients. In individuals with chronic pancreatitis, nutrition status may be further affected by poor dietary intake, often related to alcoholism. However, some deficiencies may be overlooked, potentially leading to nutrition-related problems with bone health and fatigue. The aim of this article is to describe the deficiencies that occur and to propose an evidence-based algorithm for the nutrition assessment and treatment of patients with chronic pancreatitis.

Association of gastric disease with polymorphisms in the inflammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4.

Objectives This study aimed to investigate if single nucleotide polymorphisms (SNPs) in a series of inflammatory genes were associated with the development of the most common pathologies thought to precede gastric cancer development namely; Helicobacter pylori (H. pylori)-associated gastritis and intestinal metaplasia. Methods A total of 250 patients were genotyped for 11 SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes. The study population comprised H. pylori uninfected (‘normal’) control patients (n=96), H. pylori-positive gastritis (n=91) and intestinal metaplasia patients (n=63). Genotyping was performed using Taqman allelic discrimination assays. Odds ratios for gastric disease groups were adjusted for potential confounding factors. Results No differences were identified in frequency of carriage, or homozygosity, for any of the ‘risk’ alleles investigated across the patient groups. No evidence was found to suggest an association with increased risk of developing either chronic gastritis or intestinal metaplasia with SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes or haplotypes tested. Conclusion This study found no evidence of an association with increased risk of developing either chronic gastritis or intestinal metaplasia with the SNPs or haplotypes tested.

Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn?

There is increasing scientific interest in the field of vitamin D research, moving the focus beyond bone health to other disease processes. Low circulating vitamin D levels have been reported as a risk factor for several pathophysiologically divergent diseases, including cancers, diabetes, CVD, multiple sclerosis and inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD). But, therein, remains the challenge: can any single nutrient contribute to multiple complex disease mechanisms and, ultimately, have therapeutic potential? The aim of this review is to critically evaluate several strands of scientific evidence surrounding vitamin D and inflammation, primarily focusing on IBD. Epidemiological studies suggest an increased incidence of IBD and rheumatoid arthritis in countries of more northern latitudes, mirroring sunlight patterns. A considerable body of evidence supports the anti-inflammatory effects of vitamin D, at least in animal models of IBD. Although it is accepted that suboptimal vitamin D status is common in IBD, some studies suggest that this associates with more severe disease. With regard to treatment, the data are only beginning to emerge from randomised controlled trials to suggest that people with IBD may remain in remission longer when treated with oral vitamin D. In conclusion, several strands of evidence suggest that vitamin D may modify the immune response in IBD. There is a continued need for large well-designed clinical trials and mechanistic studies to determine if, and how, this emerging promise translates into tangible clinical benefits for people with chronic debilitating diseases such as IBD.

Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant IBS.

Increased intestinal permeability and altered expression of tight junction (TJ) proteins may be implicated in the pathogenesis of irritable bowel syndrome (IBS). This study aimed to investigate the expression of adherens junction (AJ) protein E‐cadherin and TJ proteins zonula occludens (ZO)‐1 and claudin (CLD)‐1 and associations with IBS symptoms.