Shimon Reif

Tissue transglutaminase--the key player in celiac disease: a review.

Gluten-sensitive enteropathy, otherwise known as celiac sprue, is characterized by an abnormal proximal small intestinal mucosa arising as a result of an inappropriate inflammatory response to ingested gluten antigens present in wheat in genetically susceptible individuals. This immune response is directed to a 33-mer peptide of the alpha gliadin component of gluten. The generation of an epitope for the recognition by CD4+ T cells requires deamination of the protein by tissue transglutaminase (tTG). Moreover, IgA anti tTG is highly sensitive and is specific serologic marker (95-99%) of celiac disease. They can be easily determined quantitatively, by ELISA of an accurate and relatively inexpensive technique. Therefore, tTG can be used as the first line diagnostic test in the work-up of celiac disease, as well as for screening purposes. Finally, tTG may contribute to future strategies in treating celiac disease either by producing nontoxic wheat or by generating oral vaccination that can prevent the disease.

Effects of current cigarette smoking on clinical course of Crohn's disease and ulcerative colitis.

Cigarette smoking worsens Crohns disease (CD) but ameliorates ulcerative colitis (UC). In Israel, where there is no epidemiological association of smoking with CD, we examined the effects of current smoking on the course of CD and UC. Patients at nine public hospitals completed a questionnaire detailing their smoking history, disease course and treatments; subjects altering their smoking habit after the onset of disease were excluded. Sixty-four smokers and 144 nonsmokers had CD, and 34 smokers and 158 nonsmokers had UC. No differences were found between CD smokers and nonsmokers for hospitalizations, operations, and requirement for corticosteroid and immunosuppressive treatment. By contrast, UC smokers had less extensive disease than nonsmokers (P < 0.02) and fewer hospitalizations (P = 0.01) and operations (P = 0.025). Our results agree with a minority of studies showing no adverse effect of smoking on the course of CD, and confirm the protective effect of smoking in UC.

Pediatric Crohn's Disease and Growth Retardation: The Role of Genotype, Phenotype, and Disease Severity

Background. Delayed growth is a well-established feature of pediatric Crohns disease. Several factors have been shown to affect growth, including disease location, severity, and treatment. The recently discovered NOD2 gene has been correlated to ileal location of Crohns disease and subsequently could affect growth through the resulting phenotype or as an independent risk factor. The aim of our study was to determine if growth retardation is affected by genotype independently of disease location or severity. Methods. Genotyping for 3 NOD2 single-nucleotide polymorphisms was performed in 93 patients with detailed growth records. Parameters including disease location, disease severity, and NOD 2 genotype and their effect on z scores for height and weight at disease onset and during follow-up were analyzed. Results. NOD2 mutations were correlated with ileal location but not with disease severity or growth retardation. Ileal involvement was significantly associated with height retardation at disease onset and the lowest z score during follow-up. Use of steroids affected weight but not height. Regression models for growth variables revealed that the strongest association with impaired growth is with disease severity (weight- and height-failure odds ratios: 6.17 and 4.52, respectively). Conclusions. Severity of disease is correlated with growth failure for both height and weight. Location of disease is a weaker predictor of disordered growth and is correlated with growth retardation but not growth failure. The NOD2 genotype was not correlated with growth retardation or growth failure.

Lack of association between smoking and Crohn's disease but the usual association with ulcerative colitis in Jewish patients in Israel: a multicenter study

OBJECTIVE:The association between smoking and inflammatory bowel disease (IBD) is well established, but data in Jewish patients in Israel were discrepant. The aim of this study was to examine the smoking habits of Jewish IBD patients in Israel in a large scale, multicenter study.METHODS:Patients with established IBD aged 18–70 yr were interviewed in relation to smoking and other habits. Two controls (one clinic and one neighborhood control matched by age, sex, community group, and education) were sought for each subject.RESULTS:A total of 534 patients (273 ulcerative colitis [UC], and 261 Crohns disease [CD]), along with 478 clinic controls and 430 neighborhood controls, were interviewed. There was no significant difference in the smoking habits between CD patients and their controls. Of patients with CD, 24.5% were current smokers, as compared to 19.9% of clinic controls and 25.2% of neighborhood controls (NS).The odds ratio for CD in current smokers was 1.30 (95% confidence interval 0.85–1.99) versus clinic controls, and 0.96 (0.63–1.46) versus neighborhood controls. There were also no significant differences in the proportion of ex-smokers between the groups. Only12.9% of UC patients were current smokers versus 21.9. % Clinic controls, and 26.4% community controls (p < 0.005). The proportions of ex-smokers were higher in UC patients 29.7%versus 25.9%, and 19.5% in their respective controls (p < 0.001vs community controls). No significant differences were found in the proportions of never-smokers between IBD patients and controls. All the above trends were similar in four different parts of the country. The proportion of current smokers in UC decreased with the extent of disease (19.7% in proctitis, 13.6% in left-sided, and 4.5% in total colitis) (p < 0.05). Patients with UC were more likely to be light smokers(1–10 cigarettes/day), whereas patients with CD were more likely to be moderate smokers (11–20 cigarettes/day) in comparison to their controls.CONCLUSIONS:The lack of association between smoking and CD has now been established in Jewish patients in Israel. The association was found in UC. The stronger genetic tendency in CD may contribute to this discrepancy.

Nonalcoholic fatty liver disease in overweight children and adolescents

Objective: To investigate the prevalence and characteristics of non‐alcoholic fatty liver disease (NAFLD) and identify predictors for NAFLD in an overweight paediatric population.

Lack of Association Between Smoking and Inflammatory Bowel Disease in Jewish Patients in Israel

BACKGROUND/AIMS An excess of smokers in patients with Crohns disease (CD) and a paucity of smokers in patients with ulcerative colitis (UC) were reported in many studies. The aim of this study was to examine the association between smoking and inflammatory bowel disease (IBD) in Israel. METHODS Two independent studies were performed. Patients with recent IBD in comparison with matched population and outpatient controls and patients with chronic UC and CD were studied. Altogether, 475 subjects were investigated. RESULTS In both studies, the presence of current smokers was lower in CD (9% and 18%) than in UC (24% and 26%). The proportions of nonsmokers in both studies were similar (UC, 61% and 65%; CD, 67% and 70%) and comparable to those found in their two control groups (57% and 61%; 63% and 68%, respectively) and to the general population of Israel. All differences in smoking habits between patient groups and their controls were not statistically significant, except for the paucity of current smokers in the small group of patients with newly diagnosed CD (P < 0.05). A matched analysis produced similar results. CONCLUSIONS The expected associations between smoking and IBD could not be confirmed. Two hypotheses are considered: (1) the association between smoking and IBD may not be universal, and (2) our findings may be related to the higher genetic predisposition to IBD in Jewish people.

A polymorphism in the TNF-alpha promoter gene is associated with pediatric onset and colonic location of Crohn's disease.

OBJECTIVES:Studies suggest that pediatric onset of Crohns disease (CD) may demonstrate more frequent upper intestinal and colonic location and in male gender, in comparison to adults. Variability in age of onset (AOO) and location of disease have not been adequately explained to date. NOD2/CARD15 is highly expressed in the ileum, while TNF-α expression is distributed throughout the gastrointestinal tract. We hypothesized that polymorphisms that affect TNF-α function may influence variability of disease location and AOO of CD.METHODS:We evaluated two CD cohorts based on AOO (pediatric and adult onset) and 100 ethnically matched healthy controls. Patients were evaluated for AOO, disease location, and genotyped for the presence of polymorphisms in NOD2/CARD15 and in the TNF-α promoter region.RESULTS:Early AOO was associated with male gender, upper intestinal involvement, and a polymorphism in the binding site for NF-κB (TNF-863A polymorphism). NOD2 mutations and TNF-863A polymorphism had equivalent but opposite effects on disease location, with a strong combined effect (p = 0.004 corrected for multiple testing). NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p = 0.008) and positively associated with isolated colitis (OR = 2.16, p = 0.008, OR = 2.12, p = 0.03 corrected) and familial disease (p = 0.004).CONCLUSIONS:Pediatric onset of CD in our population was associated with a frequent polymorphism in the binding site for NF-κB in TNF-α promoter but not to defined NOD2/CARD15 disease-associated mutations. This polymorphism is associated with colitis and familial disease. NOD2/CARD15 mutations and the TNF-863C/A polymorphism have equivalent but opposite effects on disease location. These findings may help explain differences in CD phenotype.

Helicobacter pylori and peptic disease in the pediatric patient

The data accumulated on Helicobacter pylori infection in children suggests an important causative role of the organism in gastritis and peptic ulcer disease in this age group. The importance of eradication of H pylori in asymptomatic children in relation to its role in peptic disease and cancer in adults is debatable. This article describes the current data on bacteriologic features, pathologic spectrum, clinical significance, epidemiology, methods of diagnosis, and treatment of H pylori infection in children. Further studies will provide the information on the pathogenicity, mode of transfer, and optimal treatment of H pylori infection.

Portal vein thrombosis caused by protein C and protein S deficiency associated with cytomegalovirus infection

A 4-month-old girl who was examined because of splenomegaly had portal vein thrombosis, which apparently resulted from a combination of cytomegalovirus infection and deficiency of both protein S and protein C. The cytomegalovirus infection, by damaging endothelial cells, may have triggered a cascade of events that was ultimately expressed as portal vein thrombosis resulting from deficiency of proteins S and C.

TNF promoter polymorphisms and modulation of growth retardation and disease severity in pediatric Crohn's disease.

OBJECTIVES:Delayed growth is common in pediatric Crohns disease (CD). Multiple factors have been shown to affect growth in this situation, the most prominent being the presence and severity of inflammation and inadequate nutritional intake. Inflammation, anorexia, and weight loss are all manifestations of circulating TNF-alpha, which is elevated in CD. The ability to secrete TNF-alpha may be affected by polymorphisms in the TNF-alpha promoter. The aim of our study was to determine whether growth retardation and disease severity in pediatric onset CD are affected by TNF promoter genotype.METHODS:Genotyping for TNF-alpha and NOD2/CARD15 single nucleotide polymorphisms was performed in 87 patients with detailed growth records. Parameters including disease location and disease severity were recorded, and the effect of these polymorphisms on Z-scores for height and weight at disease onset and during follow-up were analyzed.RESULTS:Lower age of onset was linked to more height retardation, while the presence of colonic disease and the absence of ileal disease were more likely to predict the absence of growth retardation. The presence of two polymorphisms thought to decrease circulating TNF-alpha was associated with higher mean Z-scores for height and a trend toward less growth retardation. Two other polymorphisms were modestly associated with disease severity.CONCLUSION:Polymorphisms in the TNF-alpha promoter may independently modulate growth and disease severity in pediatric onset CD. The effect of these polymorphisms does not appear to be mediated via weight loss, and is relatively modest.