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Aims Clinical experience suggests that atherosclerotic disease is common in individuals with coeliac disease, but epidemiological studies have had contradicting findings. To summarise the currently available evidence, we systematically reviewed and analysed observational studies of the association of coeliac disease or dermatitis herpetiformis with coronary heart disease (CHD) or stroke. Data synthesis We searched for studies comparing CHD or stroke outcomes with individuals with and without coeliac disease or dermatitis herpetiformis. Three investigators independently searched electronic databases, identified relevant studies and extracted data. Study-specific results were combined in random-effects meta-analyses, and heterogeneity was quantified using the I 2 statistic and meta-regression. Twenty-one studies were included in our systematic review and 18 in the meta-analyses. For CHD, the pooled hazard ratio for incident disease was 1.05 (95% confidence interval (CI): 0.93, 1.19) and the overall standardised mortality ratio was 1.21 (0.99, 1.49). For stroke and brain haemorrhage, the corresponding estimates were 1.10 (95% CI: 1.00, 1.21) and 1.43 (0.97, 2.10), respectively. There was moderate to considerable heterogeneity among the study-specific estimates. In addition, many estimates were based on small numbers of outcomes and they had limitations in terms of adjustment for potential confounders. Conclusion Our meta-analyses lend some support to an association between coeliac disease and CHD or cerebrovascular disease, but the evidence base was heterogeneous and had limitations. Our systematic review highlighted a need in this area for adequately powered prospective studies with appropriate adjustment for potentially confounding factors.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease. Untreated coeliac disease patients are known to have transglutaminase 2 (TG2)-targeted IgA deposits in the small bowel mucosa. To evaluate whether similar intestinal IgA deposits are also present in DH and whether the deposits disappear with gluten-free diet, 47 untreated and 27 treated DH patients were studied. Seventy-nine percent of untreated and 41% of the treated DH patients had TG2-specific IgA deposits in the small bowel, and the presence of the deposits showed a significant association with the degree of small bowel villous atrophy (p < 0.001). Other coeliac-disease related inflammatory markers were also investigated, and the density of small bowel mucosal intraepithelial γδ(+) T cells was increased in 91% of untreated and 73% of treated DH patients. The results show that the majority of untreated DH patients have similar gluten-dependent TG2-specific IgA deposits the small bowel mucosa as coeliac disease patients.

Background and aims The diagnosis of coeliac disease is problematic in individuals not responding to a gluten-free diet. Small-bowel villous atrophy occurs in other enteropathies and non-responsive patients are often seronegative. We investigated whether small-bowel mucosal transglutaminase-2 specific autoantibody deposits distinguish non-responsive coeliac disease from other enteropathies. Methods Small-bowel mucosal autoantibody deposits were determined in 27 non-responsive, 28 responsive coeliac patients and 10 controls with other enteropathies. Of the non-responsive coeliac patients six were adhering poorly and 21 strictly to the diet; six of the 21 had enteropathy-associated lymphoma, five refractory coeliac disease and 10 otherwise persistent villous atrophy. The presence of mucosal autoantibody deposits was compared to serology, villous morphology, densities of intraepithelial lymphocytes (IELs) and markers of refractory coeliac disease. Results Twenty out of 21 well-adhering, all six poorly adhering non-responsive and all 28 untreated responsive coeliac patients had small-bowel mucosal autoantibody deposits present, while controls with other enteropathies were negative. Small-bowel mucosal autoantibody deposits were more accurate in detecting coeliac disease than serology or IEL densities. Refractory coeliac markers revealed only cases with the most severe condition. Conclusions Small-bowel mucosal autoantibody deposits differentiate coeliac disease from other enteropathies, enabling the design of appropriate therapeutic strategies.

During the past 20 years the diagnosis of coeliac disease has improved significantly. However, at the same time the true prevalence of the condition has doubled, involving more than 2% of the population in some countries. Due to mild or atypical symptoms, the diagnosis remains a challenge for the health care system. Highly sensitive and specific serum endomysial and transglutaminase-2 antibody tests are helpful in identifying patients for diagnostic endoscopy and small-bowel biopsy. The diagnosis of the disease is still based on the demonstration of gluten-induced small-bowel mucosal villous atrophy with crypt hyperplasia. However, coeliac disease may manifest itself before the development of the overt small-intestinal lesion. Positive endomysial and transglutaminase antibodies in patients with normal small-bowel mucosal villous architecture may indicate early stage coeliac disease. Currently, the only effective treatment for the condition is a life-long strict gluten-free diet. Long-term regular follow-up of patients is recommended in order to maintain good adherence to the diet. Clin Chem Lab Med 2010;48:1205–16.

Background: The seasonality of suicide rates and methods of suicide may be related to changes in weather and conditions of employment. Particularly the amount of occupational outdoor exposure could show differences in the distribution of suicides by season and the selection of suicide method, in addition to age at the time of death. Methods: The data consisted of all death certificates ( n =1359) of completed suicides in the province of Oulu, Finland, during the years 1988–1999. For male subjects included in this study, four occupational groups were identified according to decreasing occupational outdoor exposure. The mean ages, the distribution of suicide methods and the seasonal variation in suicides for each occupational group were analyzed. Results: Farmers were significantly older at the time of suicide than construction or indoor workers, and farmers employed significantly more violent methods than the other occupational groups. In the spring, farmers had a significant peak in the rate of suicides. In the winter, forest workers had a significant trough in the rate of suicides. In the summer, indoor workers had a significant peak in the rate of suicides. Limitations: The analyses were restricted to males due to the low number of females in the study population. Conclusions: The novel finding in this study was that the seasonality of violent suicides was most strongly seen as a spring peak and a winter trough among outdoor workers. The recognition of typical risk factors of different occupations, such as outdoor exposure, and occupational-related susceptibility towards certain suicide methods could benefit in the prevention of suicides.

Typical features of celiac disease are small-bowel villus atrophy, crypt hyperplasia, and inflammation which develop gradually concomitant with ingestion of gluten. In addition, patients have anti-transglutaminase 2 (TG2) autoantibodies in their serum and tissues. The aim of this study was to establish whether celiac disease can be passively transferred to mice by serum or immunoglobulins. Serum aliquots or purified immunoglobulins (Ig) were intraperitoneally injected into Hsd:Athymic Nude-Foxn1nu mice for 8 or 27 days. As mice do not have proper IgA transport from peritoneum to blood, sera with a high content of IgG class anti-TG2 antibodies from untreated IgA-deficient celiac patients were used. Mouse sera were tested for celiac disease-specific autoantibodies, and several tissues were analyzed for autoantibody deposits targeted to TG2. Morphological assessment was made of the murine small intestinal mucosa. Injection of celiac disease patient sera or total IgG led to a significant delay in weight gain and mild diarrhea in a subset of mice. The mice injected with celiac patient sera or IgG had significantly decreased villus height crypt depth (Vh/CrD) ratios and celiac disease-specific autoantibody deposits targeted to TG2 in several tissues, including the small intestine. None of these features were observed in control mice. We conclude that administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice. The experimentally induced condition in the mice injected with patient serum or IgG resembles early developing celiac disease in humans.Celiac disease patient sera or total IgG was injected into athymic mice. A significant delay in weight gain and mild diarrhea was observed. Mice evinced significantly decreased villus height crypt depth ratios. Celiac disease-specific autoantibody deposits were present in several tissues. The condition in mice resembles early stage celiac disease in humans.

Background Diagnosis of celiac disease may be problematic in that small-bowel villous atrophy sometimes occurs in conjunction with other enteropathies, develops gradually and may be patchy. Furthermore, as the often compromised quality of biopsy specimens renders diagnosis difficult, new diagnostic tools are warranted. Goals As the celiac disease-specific autoantibodies are found deposited at their production site, in the small-bowel mucosa, they may be useful in diagnostics, especially in problematic cases. We therefore systematically assessed the occurrence of celiac-specific autoantibody deposits in a large cohort of celiac patients, and established how IgA deposits decline after initiation of a gluten-free diet. Methods Transglutaminase-2 specific mucosal IgA autoantibody deposits were determined from small-bowel mucosal biopsies in 261 untreated, 71 short-term (1 y), and 105 long-term (2 to 41 y) treated celiac disease patients and in 78 nonceliac controls. The presence of the deposits was compared with celiac serology, mucosal villous morphology and density of intraepithelial lymphocytes. Results All untreated celiac disease patients had mucosal autoantibody deposits and their intensity was moderate or strong in 90% of cases. In contrast, 18% of the controls had weak depositions. During a gluten-free diet the intensity of the deposits diminished, but was still faintly positive in 56% of long-term treated celiac patients. The efficiency of the test in determining mucosal autoantibody deposits was superior to serology and inflammatory markers. Conclusions Mucosal transglutaminase-2 specific autoantibody deposits proved to be accurate gluten-dependent markers of celiac disease and would thus be of value in the diagnostics and dietary monitoring of this disorder.

Objectives: A gluten-free diet omitting wheat, rye, and barley is the only effective treatment for coeliac disease. The necessity of excluding oats from the diet has remained controversial. We studied the toxicity of oats in children with coeliac disease during a 2-year follow-up by investigating jejunal transglutaminase 2 (TG2)-targeted IgA-class autoantibody deposits, a potentially more sensitive disease marker than serum antibodies or conventional histology. Patients and Methods: Twenty-three coeliac children in remission were randomized to undergo oat or gluten challenge with wheat, rye, barley, and oats. When jejunal histological relapse was evident after gluten challenge, patients excluded wheat, rye, and barley but continued with oats. Mucosal morphology and TG2-targeted autoantibody deposits were studied in jejunal biopsies taken at baseline and after 6 and 24 months. Furthermore, serum IgA-class TG2 antibodies were measured. Results: At baseline, serum TG2 antibodies were negative in all 23 patients, but 7 of them had minor mucosal deposits. In the oats group, there was no significant change in the intensity of the deposits within 2 years. In contrast, during the gluten challenge, the intensity of the deposits clearly increased and decreased again when wheat, rye, and barley were excluded but consumption of oats was continued; this was in line with serum autoantibodies. The intensity of the mucosal deposits correlated well with both villous morphology and serum autoantibody levels. Conclusions: Consumption of oats does not induce TG2 autoantibody production at mucosal level in children with coeliac disease. Measurement of small-intestinal mucosal autoantibody deposits is suitable for monitoring treatment in coeliac patients.

Celiac disease is an autoimmune disorder wherein the ingestion of gluten causes villous atrophy of the small intestinal mucosa with crypt hyperplasia in genetically susceptible individuals. The classic symptoms are malabsorption, steatorrhea, weight loss, growth retardation, and failure to thrive (1,2). Dermatitis herpetiformis is a well-known extraintestinal manifestation of celiac disease, characterized by granular immunoglobulin A (IgA) deposits in uninvolved skin (3). Approximately 17% of celiac patients have dermatitis herpetiformis (4). Celiac disease can appear at any age after gluten has been introduced into the diet, whereas dermatitis herpetiformis usually manifests in adulthood, the median age of diagnosis being about 40 years (4). It remains obscure why some patients experience celiac disease, overt enteropathy, and no skin involvement, whereas some experience dermatitis herpetiformis with often only mild enteropathy. The following 3 case reports indicate that periods of gluten intake and gluten withdrawal may have an impact on disease expression, and the phenotype may vary in the same person over time.

In coeliac disease, immunoglobulin (Ig)A-class autoantibodies against transglutaminase-2 are produced in the small intestinal mucosa, where they are deposited extracellularly. It remains unclear whether positive intestinal transglutaminase-2-targeted IgA deposits in subjects having normal small bowel mucosal morphology are signs of early-stage coeliac disease. We evaluated the gluten dependency of these deposits in overt and mild enteropathy coeliac disease.All together 48 subjects suspected of coeliac disease but having normal small bowel mucosal villi were enrolled; 28 of them had latent coeliac disease. The remaining 20 having positive intestinal IgA deposits adopted a gluten-free diet before villous atrophy had developed. For comparison, 13 patients with overt coeliac disease and 42 noncoeliac controls were studied. Small bowel mucosal transglutaminase-2-specific autoantibodies were compared with villous morphology, intraepithelial lymphocyte densities, and serum coeliac autoantibodies.Intestinal IgA deposits were seen in all but 1 of the patients with latent coeliac disease, when the morphology was still intact; the intensity of these deposits increased as villous atrophy developed and decreased again on a gluten-free diet. In 20 patients with intestinal IgA deposits in normal villi, the intensity of the deposits decreased with the diet similarly to that seen in patients with overt coeliac disease. Mucosal IgA deposits were seen initially only in 5% of noncoeliac controls and in 8% after extended gluten consumption.The response of small bowel mucosal transglutaminase-2-specific IgA deposits for dietary intervention was similar in overt and mild enteropathy coeliac disease. Detection of such IgA deposits thus offers a good diagnostic tool to uncover early-stage coeliac disease.

Objective To establish whether children who are endomysial antibody (EmA) positive and have normal small-bowel mucosal villous morphology are truly gluten-sensitive and may benefit from early treatment with a gluten-free diet. Study design Children who were EmA positive with normal small-bowel mucosal villi were compared with children who were seropositive with villous atrophy by using several markers of untreated celiac disease. Thereafter, children with normal villous structure either continued on a normal diet or were placed on a gluten-free diet and re-investigated after 1 year. Seventeen children who were seronegative served as control subjects for baseline investigations. Results Normal villous morphology was noted in 17 children who were EmA positive, and villous atrophy was noted in 42 children who were EmA positive. These children were comparable in all measured variables regardless of the degree of enteropathy, but differed significantly from the seronegative control subjects. During the dietary intervention, in children who were EmA positive with normal villi, the disease was exacerbated in children who continued gluten consumption, whereas in all children who started the gluten-free diet, both the gastrointestinal symptoms and abnormal antibodies disappeared. Conclusions The study provided evidence that children who are EmA positive have a celiac-type disorder and benefit from early treatment despite normal mucosal structure, indicating that the diagnostic criteria for celiac disease should be re-evaluated.