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OBJECTIVES: Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD). METHODS: Six DLG5 variants (p.R30Q, P.P1371Q, P.G1066G, rs2289308, DLG-e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test. RESULTS: Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability. CONCLUSIONS: We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD.Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation.Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group.Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment.

Non-Alcohol Induced Steatohepatitis in Non-Obese Patients: Treatment With Ursodeoxycholic Acid

An increased prevalence of elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels in patients with Crohn's disease (CD) has been described. The aim of the present work was to investigate serum ASCA levels during the courses of prednisolone and mesalamine therapy in CD patients.Serum samples of 25 patients with active CD were studied for ASCA levels before as well as 2 and 9 wk after initiation of a prednisolone tapering regimen. The influence of mesalamine (4 g o.d.) on serum ASCA levels compared to that of placebo was tested over 1 yr in 38 patients (20 mesalamine and 18 placebo) participating in a postoperative prophylaxis study. Serum IgG and IgA ASCA levels were measured by ELISA. Sera of 91 CD and 40 ulcerative colitis (UC) patients as well as 334 healthy donors were tested for ASCA to recalculate new cut-off values.For IgG ASCA cut-off values were determined to be 17.0 U and 25.0 U, and for IgA ASCA 9.3 U and 14.0 U. At baseline visit, 73.0% (46/63) of patients displayed serum ASCA positivity. During prednisolone therapy, a decrease in serum IgG and IgA ASCA levels from baseline to wk 2 (p0.0001 and p0.001, respectively) as well as to wk 9 (p0.001 and p = 0.01, respectively) was observed. A trend toward an association of ASCA positivity and steroid responsiveness was calculated (p = 0.07). During mesalamine treatment, no differences in changes of ASCA levels were observed compared to placebo at any time point.ASCA are stable markers during steroid and mesalamine treatment, highlighting their reliability for use in diagnosis of CD.

Objective: Budesonide, although only topically active, is effective in the treatment of Crohn’s disease. This study was performed to compare the clinical efficacies of budesonide and prednisolone in relation to the activation status of circulating leukocytes. Methods: Twenty-four patients with active Crohn’s disease were randomized to treatment with either budesonide or 6-methylprednisolone. Clinical response was monitored by the Crohn’s disease activity index, C-reactive protein, and orosomucoid. Expression of CD25 and CD71 on T cells and CD64 on neutrophils was determined by flow cytometry. The release of TNF-α and IL-1β by peripheral blood mononuclear cells was measured by ELISA. Results: After 2 wk of treatment a clinical response was observed in both groups, but it was more accentuated in patients treated with prednisolone. At baseline an upregulation of CD71 and CD64, but not CD25, was found in active patients. Prednisolone significantly decreased the expression of CD64 and the release of TNF-α and IL-1β, but did not alter the expression of CD25 and CD71. Budesonide treatment failed to exert any effect on circulating leukocytes. Conclusions: The inability of budesonide to downregulate activated circulating leukocytes may contribute to the somewhat lower clinical efficacy of this topical steroid in the treatment of active Crohn’s disease.

Liver cirrhosis in erythropoietic protoporphyria: improvement of liver function with ursodeoxycholic acid