Evaluation of T cells in blood after a short gluten challenge for coeliac disease diagnosis

Background and aimTo diagnose coeliac disease (CD) in individuals on a gluten free diet (GFD), we aimed to assess the utility of detecting activated γδ and CD8 T cells expressing gut-homing receptors after a short gluten challenge.MethodsWe studied 15 CD patients and 35 non-CD controls, all exposed to three days of gluten when following a GFD. Peripheral blood was collected before and six days after starting gluten consumption, and the expression of CD103, β7 and CD38 in γδ and CD8 T cells was assessed by flow cytometry. Determination of IFN-γ and IP-10 was performed by means of ELISPOT and/or Luminex technology.ResultsWe observed both γδ and CD8 T cells coexpressing CD103, β7^hi and CD38 in every patient with CD on day six, but only in one control. The studied CD8 T subpopulation was easier to detect than the γδ subpopulation. Increased IFN-γ and IP-10 levels after challenge were observed in patients with CD, but not in controls.ConclusionA short three-day gluten challenge elicits the activation of CD103⁺ β7^hi CD8⁺ T cells in CD. These cells can be detected by flow cytometry in peripheral blood, opening new possibilities for CD diagnosis in individuals on a GFD.     

Non-celiac gluten sensitivity: Time for sifting the grain

In the last few years, a new nomenclature has been proposed for the disease induced by the ingestion of gluten, a protein present in wheat, rice, barley and oats. Besides celiac disease and wheat allergy, the most studied forms of gluten-related disorders characterized by an evident immune mechanism (autoimmune in celiac disease and IgE-mediated in wheat allergy), a new entity has been included, apparently not driven by an aberrant immune response: the non-celiac gluten sensitivity (NCGS). NCGS is characterized by a heterogeneous clinical picture with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving after its withdrawal from the diet. The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle. In addition, the diagnostic procedures still remain problematic due to the absence of efficient diagnostic markers; thus, diagnosis is based upon the symptomatic response to a gluten-free diet and the recurrence of symptoms after gluten reintroduction with the possibility of an important involvement of a placebo effect. The temporary withdrawal of gluten seems a reasonable therapy, but the timing of gluten reintroduction and the correct patient management approach are have not yet been determined.     

Gluten sensitivity and ‘normal’ histology: is the intestinal mucosa really normal?

BACKGROUND: Early pathogenetic events of gluten intolerance may be overlooked in patients with serologic markers of celiac disease and normal intestinal mucosa by both conventional histology and immunohistochemistry. AIMS: To investigate if a submicroscopical damage of the absorptive cell surface was associated with developing gluten sensitivity. PATIENTS AND METHODS: Duodenal biopsies of seven subjects with positive anti-endomysial antibodies and normal histology underwent ultrastructural evaluation of the epithelial surface by means of both scanning and transmission electron microscopy. Specimens of intestinal mucosa of 14 children with non-celiac conditions were used as controls. RESULTS: In four patients, electron microscopy revealed alterations of the enterocyte brush border with a significant reduction of the height of microvilli. After several months, three of them had a second biopsy that eventually showed histological modifications suggestive of celiac disease. In the other three patients, no significant alteration of enterocyte ultrastructure was observed. One of them, rebiopsied after 12 months, still showed a normal duodenal histology. CONCLUSIONS: Gluten sensitivity can be associated with 'minimal' mucosal changes not detectable with conventional light microscopy. Such lesions, which primarily involve microvillous structure, may imply a reduction of intestinal absorptive surface already in the latent stage of the disease.     

Gluten sensitive enteropathy in patients with iron deficiency anemia of unknown origin

AIM： To determine the prevalence of gluten sensitive enteropathy （GSE） in a large group of patients with iron deficiency anemia （IDA） of obscure origin.METHODS： ：In this cross-sectional study, patients with IDA of obscure origin were screened for GSE. Anti- endomysial antibody （EMA） and tissue transglutaminase antibody （tTG） levels were evaluated and duodenal biopsies were taken and scored according to the Marsh classification. The diagnosis of GSE was based on a positive serological test and abnormal duodenal histology. Gluten free diet （GFD） was advised for all the GSE patients.RESULTS： Of the 4120 IDA patients referred to our Hematology departments, 206 （95 male） patients were found to have IDA of obscure origin. Thirty out of 206 patients （14.6%） had GSE. The mean age of GSE patients was 34.6± 17.03 （range 10-72 years）. The female to male ratio was 1.3：1. Sixteen patients had Marsh 3,12 had Marsh 2, and 2 had Marsh 1 lesions. The severity of anemia was in parallel with the severity of duodenal lesions. Twenty-two GSE patients （73.3%） had no gastrointestinal symptoms. Fourteen GSE patients who adhered to GFD without receiving iron supplementation agreed to undergo follow up visits. After 6 mo of GFD, their mean hemoglobin levels （Hb） increased from 9.9 ±1.6 to 12.8 ±1.0 g/dL （P 〈 0.01）. Interestingly, in 6 out of 14 patients who had Marsh 1/2 lesions （e.g. no villous atrophy） on duodenal biopsy, mean Hb increased from 11.0 ±1.1 to 13.1 ±1.0 g/dL （P 〈 0.01） while they did not receive any iron supplementation. CONCLUSION： There is a high prevalence （e.g. 14.6%） of GSE in patients with IDA of obscure origin. Gluten free diet can improve anemia in GSE patients who have mild duodenal lesions without villous atrophy.     

Elevated serum antiphospholipid antibodies in adults with celiac disease

Background and aimsAn increased incidence of thrombosis is suggested in celiac disease. We explored serum levels of antiphospholipid antibodies in untreated and treated adult celiac disease patients.MethodsA cohort of 179 biopsy-proven celiac disease patients (89 untreated, 90 on long-term gluten-free diet) and 91 non-celiac controls underwent clinical examination, assessment of celiac serology and enzyme immunoassay testing for anticardiolipin IgG and IgM, prothrombin IgG, and phosphatidylserine-prothrombin IgG and IgM.ResultsThe level of antiphospholipid antibodies was higher in celiac disease patients compared with controls: anticardiolipin IgG 4.9 (0.7–33.8) vs 2.2 (0.4–9.6) U/ml, antiprothrombin IgG 2.9 (0.3–87.8) vs 2.1 (0.5–187.0) U/ml, antiphosphatidylserine-prothrombin IgG 6.9 (0.0–54.1) vs 2.3 (0.5–15.1) U/ml; p < 0.05 for all. Anticardiolipin IgG, antiprothrombin IgG and antiphosphatidylserine-prothrombin IgG were higher in treated compared with untreated patients. The phenotype of celiac disease at presentation (gastrointestinal symptoms, malabsorption or anemia, and extraintestinal symptoms or screen-detected disease) had no effect on the level of serum antiphospholipid antibodies.ConclusionThe serum level of antiphospholipid antibodies is increased in adults with celiac disease. The higher level of antibodies in treated patients suggests that the increase is not gluten-dependent. The prothrombotic role of antiphospholipid antibodies in celiac disease warrants further studies.     

Transglutaminase 6 antibodies in gluten neuropathy

BackgroundTG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies).MethodsThis was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy.ResultsTwenty-eight patients were recruited (mean age 62.5 ± 13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy.ConclusionsWe found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN.     

Coeliac disease: Oral ulcer prevalence, assessment of risk and association with gluten-free diet in children

AIMS: Oral mucosal lesions may be markers of chronic gastrointestinal disorders, such as those causing malabsorption. Our objectives were to assess the prevalence of recurrent oral aphthous-like ulcers in coeliac disease patients living in the Mediterranean area, and to evaluate the impact of a gluten-free diet. METHODS: A test group of 269 patients (age range 3-17 years) with coeliac disease confirmed both serologically and histologically was compared with a control group of 575 otherwise clinically healthy subjects for the presence, or a positive history of aphthous-like ulcers. Coeliac disease patients with aphthous-like ulcers were re-evaluated 1-year after starting a gluten-free diet. RESULTS: Aphthous-like ulcers were found significantly more frequently in coeliac disease, in 22.7% (61/269) of patients with coeliac disease versus 7.1% (41/575) of controls (p=<0.0001; chi-square=41.687; odds ratio=4.3123; 95% confidence interval=2.7664:6.722). Most coeliac disease patients with aphthous-like ulcers and adhering strictly to gluten-free diet (71.7%; 33/46) reported significant improvement on gluten-free diet, with no or reduced episodes of aphthous-like ulcers (p=0.0003; chi-square=13.101; odds ratio=24.67; 95% confidence interval=2.63:231.441). CONCLUSIONS: The epidemiological association found between coeliac disease and aphthous-like ulcers suggests that recurrent aphthous-like ulcers should be considered a risk indicator for coeliac disease, and that gluten-free diet leads to ulcer amelioration.     

Enfermedad celiaca en adultos chilenos

Introduction and aimTo characterize a university hospital population of Chilean adult patients with celiac disease.Patients and methodWe retrospectively reviewed the records of patients under control that were diagnosed with celiac disease through clinical characteristics, serology, and histology.ResultsA total of 149 patients were included, 119 (79.9%) of whom were women. Mean patient age was 42 years at diagnosis and 13.4% of patients had a family history of celiac disease. Mean body mass index was 24.3 kg/m², 55.3% presented with normal weight, 37.9% with overweight and obesity, and 6.8% with underweight. The main reasons for consultation were diarrhea (47%), weight loss (31%), dyspepsia (43%), and fatigue (26.1%). Anemia (26.1%), elevated transaminases (17.4%), low ferritin (11.4%), and hypovitaminosis D (9.3%) stood out, among others, in the initial laboratory work-up. The more frequent associated diseases were hypothyroidism (15.4%) and depressive disorder (11.4%). Small intestinal bacterial overgrowth was found in 10.1% and lactose malabsorption in 15.4%. The primary histologic diagnosis was celiac disease, with Marsh stage 3a villous atrophy (34.9%).ConclusionOur results were similar to those of other case series on adults, finding that celiac disease was more frequent in women, disease began in the fourth decade of life, extraintestinal symptoms predominated, and there was an association with other autoimmune diseases. An important percentage of patients were also overweight and obese.     

Enfermedad celiaca en niños del noroeste de México: características clínicas de 24 casos

BackgroundCeliac disease (CD) is an autoimmune enteropathy induced by dietary wheat gluten that can have serious consequences if not diagnosed and treated early. It is important to be familiar with other alterations associated with gluten ingestion due to the multiplicity of clinical presentations.ObjectivesTo describe the most common CD presentation patterns and alterations associated with gluten in children from the northwest region of Mexico, with an incipient knowledge of its prevalence.Patients and methodsAge, sex, family history, and gastrointestinal and extraintestinal symptoms were recorded in 24 patients within the time frame of 2006 to 2010. Biochemical and hematologic data were collected. Anti-gliadin and anti-transglutaminase antibodies were analyzed in all the cases, and haplotypes (HLA-DQ2/DQ8) and duodenal biopsy were evaluated in some of the cases.ResultsOf the 24 patients (14 girls and 10 boys), 13 presented with typical CD with symptoms of poor gastrointestinal absorption; 7 patients with a mean age of 5 years presented with atypical CD; 2 had disease onset with gastrointestinal and extraintestinal (neurologic) problems; and 2 with other gluten-related disorders. All of the patients had positive serology; 11/15 presented with HLA-DQ2/DQ8 and 4 with at least one allele; damaged mucosa was observed in the 6 biopsies taken. A third of the patients were anemic, 6 presented with an albumin value of < 3.5 g/dL, and 4 with mineral deficiencies. A total of 83% of the patients improved with a gluten-free diet.ConclusionsThe presentation patterns were: 1) typical CD, 2) atypical CD, 3) CD with gastrointestinal and extraintestinal (neurologic) symptoms, and 4) gluten-related disorders other than CD.     

Pulmonary Hemosiderosis in Association with Celiac Disease

A 15-year-old male had a history of increasing dyspnea on exertion, cough, sputum production, fever, weakness, hemoptysis, and diarrhea. Chest radiography demonstrated bilateral alveolar consolidation. Bronchoalveolar lavage fluid analysis revealed extensive hemosiderin-laden alveolar macrophages. On the basis of iron deficiency anemia, diarrhea, raised antigliadin and antiendomysial antibodies, widespread villous atrophy, and crypt hyperplasia on intestinal biopsy, celiac disease was diagnosed. After treatment with a gluten-free diet, all his clinical symptoms and radiographic findings improved within two weeks.     

Correlation of Clinical and Histopathological with Endoscopic Findings of Celiac Disease in the Turkish Population

Endoscopic findings have been described for the diagnosis of celiac disease but the relationship amond the clinical presentation, endoscopic markers, and the degree of histopathological findings is not clear. Thirty patients who were thought to have celiac disease were included in this study. Biopsies taken from the duodenum were examined histopathologically. The relationship among the endoscopic, clinical, and histopathological findings were investigated. Partial villous atrophy was seen in 14 patients (46.6%), and subtotal and total villous atrophy were seen in 6 (20%) patients each. Eighty six percent of patients with a mosaic appearance, 76% of patients with the finding of loss of folds, and 90% of patients with scalloping on endoscopy had either partial villous atrophy, subtotal villous atrophy, or total villous atrophy on biopsy. We conclude that endoscopic findings in celiac disease can reveal valuable information both for diagnosis and for demonstration of the severity of the disease state.     

Malignancy and mortality in a population-based cohort of patients with coeliac disease or‘gluten sensitivity＇

AIM: To determine the risk of malignancy and mortality in patients with a positive endomysial or anti-gliadin antibody test in Northern Ireland. METHODS: A population-based retrospective cohort study design was used. Laboratory test results used in the diagnosis of coeliac disease were obtained from the Regional Immunology Laboratory, cancer statistics from the Northern Ireland Cancer Registry and mortality statistics from the General Registrar Office, Northern Ireland. Age standardized incidence ratios of malignant neoplasms and standardized mortality ratios of all-cause and cause-specific mortality were calculated. RESULTS: A total of 13 338 people had an endomysial antibody and/or an anti-gliadin antibody test in Northern Ireland between 1993 and 1996. There were 490 patients who tested positive for endomysial antibodies and they were assumed to have coeliac disease. There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive. Malignant neoplasms were not significantly associated with coeliac disease; however, all-cause mortality was significantly increased following diagnosis. The standardized incidence and mortality ratios for non-Hodgkin's lymphoma were increased in coeliac disease patients but did not reach statistical significance. Lung and breast cancer incidence were significantly lower and all-cause mortality, mortality from malignant neoplasms, non-Hodgkin's lymphoma and digestive system disorders were significantly higher in gluten sensitive patients compared to the Northern Ireland population. CONCLUSION: Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies. Breast cancer is significantly reduced in the cohort of patients with gluten sensitivity.     

Celiac disease: Alternatives to a gluten free diet

Celiac disease is a chronic inflammatory disorder of the small intestine caused by the ingestion of gluten or related rye and barley proteins. At present, the only available treatment is a strict gluten-exclusion diet. However, recent understanding of the molecular basis for this disorder has improved and enabled the identification of targets for new therapies. This article aims to critically summarize these recent studies.     

Association of Gluten Enteropathy and Irritable Bowel Syndrome in Adult Turkish Population

PURPOSE: Irritable bowel syndrome is generally diagnosed according to the symptoms of the patient, and gluten enteropathy can also be presented with similar symptoms (diarrhea and/or constipation) of irritable bowel syndrome. Aimed to assess the association and the frequency of gluten enteropathy in a group of Turkish patients diagnosed as irritable bowel syndrome. RESULTS: Found anti-gliadin IgA positivity only in four patients among patients with irritable bowel syndrome. However, none of these four patients had anti-endomycium positivity or any histopathological findings specific for gluten enteropathy. All these four patients had normal histology in their small bowel biopsies. CONCLUSION: Irritable bowel syndrome is a common problem in the population, but gluten enteropathy is not associated with the vast majority of subjects with irritable bowel syndrome as expected. The need for screening gluten enteropathy among these patients is still unclear, and screening with serology only without small bowel biopsy may lead to false positive results.