Cytokine gene polymorphism in microscopic colitis association with the IL-6-174 GG genotype.

OBJECTIVES: Microscopic colitis (MC) is a chronic inflammatory disease with unknown pathogenesis. Very little is known about polymorphisms in the cytokine genes in MC. We have investigated the occurrence of well-characterized polymorphisms of interleukins (IL-6, IL-1ß, IL-1 receptor antagonist, IL-10) and CD14 in MC. We also determined the serum IL-6 levels. METHODS: We genotyped 81 patients with MC and 178 controls for polymorphisms of IL-6-174, IL-1ß-511, IL-1ß-3953, IL-1 receptor antagonist, IL-10-1082 and CD14-159. Serum concentration of IL-6 was measured in 72 patients. RESULTS: Genotype GG of IL-6-174 was more prevalent in MC compared with the controls (P=0.030; odds ratio: 1.941; confidence interval: 1.078-3.495), and the frequency of allele G of IL-6-174 was higher in MC (0.55 vs. 0.47; P=0.036; odds ratio: 1.514; confidence interval: 1.041-2.203). However, after correction for multiple comparisons, the difference became nonsignificant. IL-6 genotype and the serum IL-6 concentration showed no association. The concentration of IL-6 was higher in patients with collagenous colitis than in those with lymphocytic colitis (median 1.73 vs. 1.34 pg/ml, P=0.011). No association between polymorphisms of other cytokine genes and MC was seen. CONCLUSION: The IL-6-174 gene polymorphism has a possible association with MC, as the IL-6 GG genotype was more frequent in patients with the disease. As this genotype may be linked with an enhanced IL-6 production, we speculate that this polymorphism can influence the pathogenesis of MC by evoking a proinflammatory bias in the mucosal cytokines. The enhanced concentration of IL-6 in collagenous colitis compared with lymphocytic colitis supports a difference in the pathogenetic mechanisms between the two subgroups of MC.

Gastroduodenal mucosa in microscopic colitis.

BACKGROUND: We have assessed gastroduodenal, endoscopical and histopathological findings in a series of patients with microscopic colitis (MC). METHODS: We studied 75 patients with MC, 27 with collagenous colitis (CC) and 48 with lymphocytic colitis (LC), and 60 controls. Data of endoscopical findings were collected and biopsies were assessed. RESULTS: Helicobacter pylori infection rate was 15% in MC and 28% in the controls (p = 0.088). Age at diagnosis of MC was higher in H. pylori positive than negative patients (63.4 ± 9.6 vs. 54.4 ± 13.1 years; p = 0.034). Gastric endoscopic erosions were more prevalent in CC than in LC (25.9% vs. 6.2%; p = 0.030) and associated with thick body glands and antral predominance of gastritis in H. pylori positive patients. Rates of focal gastritis (5.6% vs. 6.9%) and lymphocytic gastritis (5.6% vs. 10%) were similar in MC and controls. LC was associated with gastric epithelial lymphocytosis and lymphocytic gastritis. Fifteen patients (20%) had celiac disease. CONCLUSIONS: Unlike LC, CC is associated with endoscopic erosions, likely related with the high acid secretion capacity as indicated by the ample body glands and antral predominance of gastritis in H. pylori associated cases of CC. The presence of some divergent gastroduodenal features in LC and CC, and in comparison with those reported in inflammatory bowel disease (IBD), supports the concept that these two conditions differ not only from IBD but also from each other. The findings also suggest the presence of pathogenetic links between colorectal and gastroduodenal abnormalities.

[Update on current care guidelines. Safe use of non-steroidal anti-inflammatory drugs]. / Tulehduskipulääkkeiden turvallinen käyttö.

Pain medication should be based on patient's needs and risk profile. Age > 65 years, prior ulcer, co-morbidities, large daily dose, Helicobacter pylori infection, concurrent use of glucocorticoids, serotonin re-uptake inhibitors, or warfarin increase the risk of upper gastrointestinal bleeds. As a preventive strategy the use of concurrent proton pump inhibitors with non-selective NSAIDs is recommended. It is also possible to use COX-2 selective NSAIDs but they are contraindicated for persons with atherosclerotic diseases and special consideration is required for persons with risk factors of heart diseases. Paracetamol is the drug of choice for pain.

Human leucocyte antigen and TNFalpha polymorphism association in microscopic colitis.

OBJECTIVES: Coeliac disease (CD) is common in patients with microscopic colitis (MC). The human leucocyte antigen (HLA)-DR3-DQ2 haplotype is strongly associated with CD, and there is evidence for an association with MC. We analysed the genetic background of MC by assessing the haplotypes of HLA-DR3-DQ2 and HLA-DR4-DQ8. In addition, TNFalpha gene polymorphism (-308) associated with susceptibility to several autoimmune diseases was studied. METHODS: Eighty patients with MC including 29 with collagenous colitis (CC) and 51 with lymphocytic colitis (LC) were typed for HLA-DR3-DQ2, and HLA-DR4-DQ8 molecule encoding genes using either an allele-specific PCR, or hybridization with sequence-specific oligonucleotides. Duodenal biopsies (N=78) confirmed the diagnosis of CD in 15 (18.8%) patients. TNFalpha(308) alleles were analyzed in 78 patients with MC (27 with CC and 51 with LC). A control group of 3627 patients was used in the HLA study and 178 patients in the TNFalpha study. RESULTS: HLA-DR3-DQ2 haplotype was more frequent in patients with MC (43.8%) including both subgroups (LC, 44.8%; CC, 43.1%; P<0.001), and MC with CD (86.7%; P<0.001) and without CD (33.3%; P=0.003), compared with the controls (18.1%). Similarly, the TNF2 carrier rate was higher in MC (46.2%; P<0.001) including both CC (44.4%; P=0.031) and LC (47.1%; P=0.001), and both MC patients with CD (66.7%; P=0.001) and without CD (39.3%; P=0.019), compared with the controls (23%). CONCLUSION: Both CC and LC are associated with the HLA-DR3-DQ2 haplotype and with TNF2 allele carriage. These associations are present also in MC patients without CD. The shared predisposing HLA-DR3-DQ2 haplotype and the high prevalence of CD in patients with MC suggest an epidemiological overlap, and probably some similarities in the pathogenesis of CD and MC.

Epithelial cell proliferation and glandular atrophy in lymphocytic gastritis: effect of H pylori treatment.

AIM: Lymphocytic gastritis is commonly associated with Helicobacter pylori infection. The presence of glandular atrophy and foveolar hyperplasia in lymphocytic gastritis suggests abnormalities in cell proliferation and differentiation, forming a potential link with the suspected association with gastric cancer. Our aim was to compare epithelial cell proliferation and morphology in H pylori associated lymphocytic gastritis and H pylori gastritis without features of lymphocytic gastritis, and to evaluate the effect of H pylori treatment. METHODS: We studied 14 lymphocytic gastritis patients with H pylori infection. For controls, we selected 14 matched dyspeptic patients participating in another treatment trial whose H pylori infection had successfully been eradicated. Both groups were treated with a triple therapy and followed up with biopsies for 6-18 months (patients) or 3 months (controls). Blinded evaluation for histopathological features was carried out. To determine the cell proliferation index, the sections were labeled with Ki-67 antibody. RESULTS: Before treatment, lymphocytic gastritis was characterized by foveolar hyperplasia (P=0.001) and glandular atrophy in the body (P=0.008), and increased proliferation in both the body (P=0.001) and antrum (P=0.002). Proliferation correlated with foveolar hyperplasia and inflammation activity. After eradication therapy, the number of intraepithelial lymphocytes decreased in the body (P=0.004) and antrum (P=0.065), remaining higher than in controls (P<0.001). Simultaneously, the proliferation index decreased in the body from 0.38 to 0.15 (P=0.043), and in the antrum from 0.34 to 0.20 (P=0.069), the antral index still being higher in lymphocytic gastritis than in controls (P=0.010). Foveolar hyperplasia and glandular atrophy in the body improved (P=0.021), reaching the non-LG level. CONCLUSION: In lymphocytic gastritis, excessive epithelial cell proliferation is predominantly present in the body, where it associates with foveolar hyperplasia and glandular atrophy. These characteristic changes of lymphocytic gastritis are largely related to H pylori infection, as shown by their improvement after eradication. However, some residual deviation was still seen in lymphocytic gastritis, indicating either an abnormally slow improvement or the presence of some persistent abnormality.

Apolipoprotein E and colon cancer. Expression in normal and malignant human intestine and effect on cultured human colonic adenocarcinoma cells.

Background: Apolipoprotein E (apo E) is a key regulatory protein in lipoprotein metabolism and it is also a potent inhibitor of cell proliferation. Although genetic alterations of apo E affect enterohepatic cholesterol transport and, presumably, the risk of colon carcinoma, the expression and potential functions of apo E in the human intestine are poorly known. Methods: The localization of apo E in normal and malignant gastrointestinal tract was studied using immunohistochemistry and in situ hybridization. The effect of apo E3 on cell polarity and the distribution of beta-catenin was examined in HT29 human colon adenocarcinoma cell lines. Results: Both apo E protein and mRNA were present throughout human intestine. The macrophages in the superficial lamina propria of normal colon were more strongly positive for apo E than those in the small intestine, where the most positively stained cells were dendritic cells and macrophages in the germinal centers of lymphoid follicles. In carcinomas, intensely positive macrophages surrounded the tumor area. In cultured undifferentiated HT29 cells, treatment with apo E improved cell polarity and translocated beta-catenin from the cytoplasm to cell--cell adhesion sites. Conclusions: Mononuclear phagocytes and endocrine cells are the main source of apo E in the gastrointestinal tract. We hypothesize that macrophage-derived apo E may modulate epithelial integrity and thus contribute to cell growth.