Small Bowel Villous Atrophy Research Articles

Mesenchymal Stromal Cell Infusions as Rescue Therapy for Corticosteroid-Refractory Adult Autoimmune Enteropathy

Adult autoimmune enteropathy (AIE) is a rare cause of malabsorption syndrome unresponsive to dietary restriction. Its diagnostic hallmarks are small-bowel villous atrophy and antienterocyte autoantibodies. Therapy is based mainly on nutritional support and immunosuppression. We treated a 61-year-old woman with corticosteroid-refractory AIE and life-threatening malabsorption syndrome with systemic infusions of autologous, bone marrow–derived, mesenchymal stromal cells (MSCs) as rescue therapy. The MSCs were expanded ex vivo following a previously used Good Manufacturing Practice procedure, and 2 intravenous infusions of 1.8 × 106 MSCs/kg body weight were administered 2 weeks apart. Analysis of circulating and mucosal regulatory T-and B-cell numbers, and of serum and secretory immunoglobulin levels, was performed before and after treatment. The MSC infusions were safe and effective, leading to disappearance of disease hallmarks and recovery from the life-threatening condition. Increases in mucosal regulatory T-cell numbers and secretory immunoglobulin levels were also observed. The benefit, however, was transient, and a further MSC infusion resulted in the same short efficacy. This case encourages the use of MSCs to treat patients with life-threatening, corticosteroid-refractory AIE and suggests that MSC infusion can attenuate, albeit transiently, the autoimmune attack.

PTU-158 Coeliac disease investigation and follow-up

IntroductionCoeliac disease (CD) is an abnormal immune response to gluten affecting 1% of the UK population, resulting in small bowel villous atrophy, malabsorption and GI symptoms. A large number of...

Chronic Diarrhea in Children

Chronic Diarrhea in Children

In vitromodels for gluten toxicity: relevance for celiac disease pathogenesis and development of novel treatment options

In genetically predisposed individuals, dietary gluten in wheat, rye and barley triggers celiac disease, a systemic autoimmune disorder hallmarked by an extensive small-bowel mucosal immune response. The current conception of celiac disease pathogenesis is that it involves components of both innate and adaptive immunity whose activation typically leads to small-bowel villous atrophy with crypt hyperplasia. Currently, the only effective treatment for celiac disease is a strict lifelong gluten-free diet excluding all wheat-, rye- and barley-containing food products. During the diet, the clinical symptoms improve and the small-bowel mucosal damage recovers, while re-introduction of gluten into the diet leads to re-appearance of the symptoms and deterioration of the small-bowel mucosal architecture. In view of the restricted nature of the diet, alternative treatment is warranted. Improved understanding of the molecular basis of celiac disease has enabled researchers to suggest other therapeutic approaches. Although there is no animal model reproducing all features of celiac disease, the use of in vitro approaches including a variety of cell lines and the celiac patient small-bowel mucosal biopsy organ culture has generated knowledge about pathogenesis of celiac disease. In these culture systems, gluten induces different effects that can be quantified, thus also enabling studies concerning the efficacy of candidate therapeutic compounds for celiac disease. This review describes the intestinal epithelial cell models, celiac patient T-cell lines and clones, as well as the small-bowel mucosal organ culture methods widely used in studies of celiac disease, and summarizes the major findings obtained with these systems.

Celiac disease: Prevalence, diagnosis, pathogenesis and treatment

Celiac disease (CD) is one of the most common diseases, resulting from both environmental (gluten) and genetic factors [human leukocyte antigen (HLA) and non-HLA genes]. The prevalence of CD has been estimated to approximate 0.5%-1% in different parts of the world. However, the population with diabetes, autoimmune disorder or relatives of CD individuals have even higher risk for the development of CD, at least in part, because of shared HLA typing. Gliadin gains access to the basal surface of the epithelium, and interact directly with the immune system, via both trans- and para-cellular routes. From a diagnostic perspective, symptoms may be viewed as either "typical" or "atypical". In both positive serological screening results suggestive of CD, should lead to small bowel biopsy followed by a favourable clinical and serological response to the gluten-free diet (GFD) to confirm the diagnosis. Positive anti-tissue transglutaminase antibody or anti-endomysial antibody during the clinical course helps to confirm the diagnosis of CD because of their over 99% specificities when small bowel villous atrophy is present on biopsy. Currently, the only treatment available for CD individuals is a strict life-long GFD. A greater understanding of the pathogenesis of CD allows alternative future CD treatments to hydrolyse toxic gliadin peptide, prevent toxic gliadin peptide absorption, blockage of selective deamidation of specific glutamine residues by tissue, restore immune tolerance towards gluten, modulation of immune response to dietary gliadin, and restoration of intestinal architecture.

Chronic Gastritis in Dermatitis Herpetiformis: A Controlled Study

Background and Objective. Previous small studies suggest that chronic atrophic gastritis is common in dermatitis herpetiformis (DH). We here examined the frequency and topography of chronic gastritis in 93 untreated DH subjects and in 186 controls with dyspepsia. Methods. Specimens were drawn from the gastric corpus and antrum and examined for atrophy, intestinal metaplasia, and Helicobacter pylori. Duodenal biopsies were taken. Results. Atrophic corpus gastritis was more frequent in DH than in controls (16.0% and 2.7%, resp., P < 0.001); atrophy in the antrum was rare in both groups (3.2% and 1.1%, P = 0.34). Intestinal metaplasia was present in 13 (14.0%) DH and 12 (6.5%) control patients (P = 0.038) and H. pylori in 17 (18.3%) and 17 (9.3%) (P = 0.028), respectively. Small-bowel villous atrophy was seen in 76% of the DH patients, equally in patients with and without chronic gastritis. One DH patient with atrophic gastritis developed gastric cancer. Conclusion. In DH, chronic atrophic gastritis was common in the corpus, but not in the antrum. H. pylori will partly explain this, but corpus atrophy is suggestive of an autoimmune etiology. Atrophic gastritis may increase the risk of gastric cancer. We advocate performing upper endoscopy with sufficient histologic samples in DH.

Potential confounders in observed association between coeliac disease and tuberculosis

Sirs, I read with interest the article by Ludvigsson et al.1 The authors have convincingly established the incidence of tuberculosis to be higher in patients with coeliac disease and evidence of villous atrophy. In their case control study of 29 026 patients, they noted a doubling [HR 2.0 (CI = 1.3–3.0)] in risk of tuberculosis. The risk was the highest in the first year after diagnosis of tuberculosis and, interestingly, the risk was similar in those with milder histological lesions {Marsh I and II [HR 1.9 (1.2–3.1)]}. Although absolute risk was small (10/100 000) the findings provide a further insight into the risks coeliac disease may pose. The authors are to be congratulated on their thorough evaluation of the proposed mechanisms, although the dietary intake of vitamin D in a gluten-free diet may not be as low as the author’s claim.2 In addition, absorption of vitamin D from the gut is believed to be a minor contributor to total body vitamin D. The intestinal manifestations of tuberculosis can vary markedly,3 but it is a recognised cause of small bowel villous atrophy.4 Equally, co-infection with HIV (itself a cause of enteropathy) and tuberculosis may be relevant given the small absolute incidence of tuberculosis in the populations analysed, and the 0.1% prevalence of HIV in Sweden.5 Furthermore, gastrointestinal symptoms are not infrequent in treatment for tuberculosis and may have led to an increased investigation of this population. This may at least partly explain the increased incidence seen within the first 12 months of diagnosis [HR 3.5 (1.5–8.4)] and contribute to biases identified by the authors in earlier publications.6 Could the authors elaborate on the potential confounder of intestinal inflammation as an extra-thoracic manifestation of tuberculosis and the potential contribution of HIV co-infection to the hazard ratios described? Declaration of personal and funding interests: None.

Usefulness of Small-bowel Mucosal Transglutaminase-2 Specific Autoantibody Deposits in the Diagnosis and Follow-up of Celiac Disease

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. 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. 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. 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. 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.

Plasma citrulline as a quantitative biomarker of HIV-associated villous atrophy in a tropical enteropathy population

Studies have shown that the circulating citrulline concentration is decreased in patients with proximal small bowel villous atrophy from coeliac disease and more so in patients with extensive damage to the intestinal mucosa, but there have been few data on HIV enteritis and tropical enteropathy (TE). Our primary aim was to correlate serum citrulline with the degree of reduction of the enterocyte mass in HIV-infected patients with TE. Postabsorptive fasting serum citrulline was measured in 150 TE pts, 44 of whom had HIV infection, using reverse phase, high performance liquid chromatography. Absorptive capacity and permeability were measured after intrajejunal instillation of 4 sugars (5 g lactulose, 1 g L-rhamnose, 0.5 g D-xylose, 0.2 g 3-O methyl D glucose) with assay by thin-layer chromatography. Morphometric analysis was carried out on jejunal biopsies. In HIV positive patients, the median serum citrulline was significantly lower (median 19, interquartile range (IQR) 17-24 μmol/L) than in HIV negative patients (median 27, IQR 23-33 μmol/L; p < 0.001). There were statistically significant correlations (p < 0.005) between citrulline and: crypt depth; villous height/crypt depth ratio; Shenk-Klipstein score; and xylose absoption, only in the HIV positive. Serum citrulline concentration appears to be a quantitative biomarker of small bowel mass integrity in HIV positive enteropathy and deserves assessment as a surrogate for monitoring anti-retroviral therapy.

Intestinal transglutaminase 2 specific antibody deposits in non-responsive coeliac disease

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.

Gastrointestinal symptoms, quality of life and bone mineral density in mild enteropathic coeliac disease: A prospective clinical trial

Objective. The diagnosis of coeliac disease requires small-bowel mucosal villous atrophy with crypt hyperplasia. However, patients with endomysial antibodies but structurally normal villi may suffer from a disorder similar to those with villous atrophy. The aim of this study was to evaluate gastrointestinal symptoms, quality of life and bone mineral density in patients with mild enteropathy, and the effect of a gluten-free diet. Material and methods. A prospective trial was carried out in 73 adults having endomysial antibodies with normal villous morphology (Marsh I–II; mild enteropathy) or villous atrophy (Marsh III). Gastrointestinal symptoms and quality of life were surveyed by means of structured questionnaires and bone mineral density by means of X-ray absorptiometry. Altogether, 110 subjects served as non-coeliac controls. Results. At baseline, patients with mild enteropathy evinced more gastrointestinal symptoms than non-coeliac controls, but there were no significant differences in quality of life between the groups. After 1 year on a gluten-free diet, indigestion and depression were significantly alleviated in the mild enteropathy group. Osteoporosis or osteopenia was detected in 58% of subjects in the mild enteropathy group and there was a trend towards improved bone mineral density after the treatment. Conclusions. Endomysial antibody-positive patients with normal villous structure may suffer from gastrointestinal symptoms and have poor bone health. Furthermore, they benefit from a gluten-free diet similar to those with overt villous atrophy.

The Complexity of Celiac Disease

Positive celiac antibodies and small-bowel mucosal villous atrophy are diagnostic criteria for classic celiac disease. But do antibody-positive children with normal villous structure also benefit from a gluten-free diet? To find out, investigators in Finland followed children who were referred because of suspicion of celiac disease (symptoms included …

Serum fatty acid profile in celiac disease patients before and after a gluten-free diet

Objective. Celiac disease (CD) is characterized by villous atrophy with crypt hyperplasia and inflammation of the small intestinal mucosa leading to disturbed epithelial transport. In untreated CD, fat malabsorption can occur. The aim of this study was to investigate the profile of serum fatty acids in newly detected CD before and after treatment with a gluten-free diet. Material and methods. Serum samples were obtained from 50 adults with active CD showing small-bowel mucosal villous atrophy, from the same patients in remission after treatment with a gluten-free diet, and from 59 controls. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Results. Especially the proportions of arachidonic acid (20:4 n-6) and the long-chain polyunsaturated fatty acids of the n-3 family docosapentaenoic acid (22:5 n-3) and docosahexaenoic acid (22:6 n-3) were decreased in subjects with active CD. Serum levels of these fatty acids increased during remission, but still remained significantly lower than control values. Levels of unsaturated and monounsaturated fatty acids were generally increased in subjects with CD compared with those in controls. Conclusions. In patients with CD, determination of serum fatty acid composition can be considered if the dietary history or symptoms suggest an inadequate supply of long-chain fatty acids.

High rates of complications and substantial mortality in both types of refractory sprue

Refractory sprue (RS) is a rare malabsorption syndrome defined by persisting small bowel villous atrophy despite a strict gluten-free diet. The clinical picture and long-term outcome of RS is highly variable and is not well described. To define underlying and accompanying diseases and clinical outcome in consecutive patients with RS. Clinical and histological data from patients with RS at our department were analyzed retrospectively. RS was defined as villous atrophy and malabsorption despite a strict gluten-free diet persisting without improvement for more than 6 months or requiring earlier therapeutic intervention. Thirty-two patients with RS were identified (23 RS type I, nine RS type II). Follow-up period was 55 (12-372) months. Two patients progressed from RS type I into type II. Thrombembolic events occurred in nine cases, and additional autoimmune diseases were found in 17 patients. Overt intestinal T-cell lymphoma developed in four patients with RS type II. Three patients with RS type II died during the observation period owing to intestinal T-cell lymphoma and four with RS type I owing to infectious complications. Five-year cumulative survival was 90% (95% confidence interval 76-100) in patients with RS type I and higher than in patients with RS type II (53%, 12-94%; P<0.05). RS comprises a very heterogenous group of patients with long-term survival seen even in single patients with RS type II. Overall, survival is shorter in RS type II in comparison with RS type I. Patients with RS type I, however, show similar rates of disease-related complications as well as substantial mortality.

Serologic screening for coeliac disease in risk groups: Is once in the lifetime enough?

It is well established that coeliac disease with mucosal inflammation, small bowel villous atrophy and crypt hyperplasia may develop by time [1]. This has been clearly shown in individuals positive for serum endomysial or transglutaminase antibodies and normal small bowel mucosa [2,3], whereas the data are scanty in those with negative coeliac antibodies. However, evidence suggests initially seronegative people may become seropositive and subsequently develop coeliac disease. This has been shown in especially type 1 diabetes mellitus, a well-known risk group for coeliac disease: Mäki et al.

Adult Autoimmune Enteropathy: Mayo Clinic Rochester Experience

Autoimmune enteropathy is a rare cause of intractable diarrhea associated with circulating gut autoantibodies and a predisposition to autoimmunity. It is rarely observed in adults, with only 11 cases reported to date. Fifteen adults with autoimmune enteropathy were identified at the Mayo Clinic, Rochester, from May 2001-June 2006. The demographic, clinical, and treatment data were abstracted from their records. The study population was 87% white, 47% female, with median age of 55 years (interquartile range, 42-67 years). All patients had protracted diarrhea, weight loss, and malnutrition. Celiac disease was excluded by lack of response to gluten-free diet or absence of the celiac disease susceptibility HLA genotypes. Fourteen patients were tested for gut epithelial cell antibodies, and 93% were positive for anti-enterocyte and/or anti-goblet cell antibodies. Predisposition to autoimmune diseases was noted in 80%, as indicated by a variety of circulating autoantibodies. Small intestinal histopathologic findings included subtotal villous atrophy and lymphoplasmacytic infiltration in the lamina propria with relatively few surface intraepithelial lymphocytes. T-cell receptor gene rearrangement studies were negative in all cases. Immunosuppressive therapy was required in 93% of cases. Clinical improvement was noted in 60% after 1-8 weeks of steroid therapy. Autoimmune enteropathy is a heterogeneous disease and should be considered in the differential diagnosis of malabsorption and small bowel villous atrophy. The presence of gut epithelial cell antibodies can help confirm the diagnosis. No single agent is unequivocally effective in inducing remission, and immunosuppressive therapy is required in most cases.

Celiac disease manifested by polyneuropathy and swollen ankles

A 27-year-old male started to have his ankles swollen during his military service. He was examined at a military hospital where electromyoneurography showed the signs of distal sensory-motor polyneuropathy with axon demyelinization and weak myopathic changes, whereas histopathological examination of gastrocnemius muscle biopsy revealed some mild and nonspecific myopathy. Besides, he was found to have subcutaneous ankle tissue edemas and hypertransaminasemia. Due to these reasons, he was dismissed from the military service and examined at another hospital where bone osteodensitometry revealed low bone mineral density of the spine. However, his medical problems were not resolved and after the second discharge from hospital he was desperately seeing doctors from time to time. Finally, at our institution he was shown to have celiac disease (CD) by positive serology (antitissue transglutaminase and antiendomysial antibodies) and small bowel mucosal histopathological examination, which showed total small bowel villous atrophy. Three months after the initiation of gluten-free diet, his ankle edema disappeared, electromyoneurographic signs of polyneuropathy improved and liver aminotransferases normalized. Good knowledge of CD extraintestinal signs and serologic screening are essential for early CD recognition and therapy.

The prevalence of coeliac disease in adult Danish patients with type 1 diabetes with and without nephropathy

To the Editor: Coeliac disease causes malabsorption due to small bowel villous atrophy, which normalises when gluten, which is found in wheat, rye and barley, is withdrawn from the diet. Coeliac patients should be treated with a gluten-free diet that corrects the intestinal malabsorption and protects against the development of osteoporosis and intestinal lymphoma. As shown in several studies (review [1]), type 1 diabetes is associated with a high prevalence (2–10%) of coeliac disease. This has, in part, been explained by genetic factors, in particular by increased frequencies of HLA-DR3 and HLA-DQ2 [2]. Coeliac symptoms are often absent or atypical in type 1 diabetic patients and the diagnosis is therefore often delayed. Diabetic nephropathy is the leading cause of end-stage renal disease and develops in approximately one-third of type 1 diabetic patients within the first 20 years of diabetes. The pathogenesis of diabetic nephropathy is only partially understood. In addition to genetic factors, haemodynamic, metabolic and growth factors are generally accepted to contribute [3]. As in diabetic nephropathy [4], reduced final height is a significant clinical manifestation of coeliac disease. In this study we investigated the prevalence of coeliac disease in adult Danish type 1 diabetes patients, with the specific aim of studying whether undiagnosed coeliac disease is more prevalent in type 1 diabetic patients with diabetic nephropathy than in type 1 diabetic patients without nephropathy. We studied 967 type 1 diabetic patients [5]. The patient population comprised a group of 462 patients with overt diabetic nephropathy (defined as persistent macroalbuminuria [>300 mg/24 h], retinopathy and no signs of other kidney or urinary tract disease; 284 men, median age 41 [range: 17–78] years, median serum creatinine 103 [range: 52–706] μmol/l) and a group of 505 patients with longstanding (23 [range: 10–63] years) type 1 diabetes and persistent normoalbuminuria (275 men, age 46 [range: 20– 81] years). Median age at onset of diabetes was 12 (range: 0–47) and 18 (range: 0–64) years in the nephropathy and normoalbuminuric groups respectively (p<0.001). Total serum IgA concentration (in-house ELISA; Statens Serum Institute, Copenhagen, Denmark) and IgA anti-transglutaminase concentration (anti-tTG, commercial ELISA, Celikey; Pharmacia, Freiburg, Germany) were measured in a single random blood sample. The specificity and sensitivity values of the IgA anti-tTG assays were 99 and 96% respectively. The presence of IgA anti-tTG is highly indicative of coeliac disease even in asymptomatic cases [6]. Patients positive after screening were referred to their local hospital for a possible small bowel biopsy procedure and instructions for a gluten-free diet. Sera from five subjects with IgA deficiency (<0.1 mg/ml) were analysed for IgG anti-gliadin antibodies and IgG anti-tTG. We collected clinical data and laboratory results using a questionnaire including questions concerning possible earlier diagnosis of coeliac disease and possible previous gluten-free diet. H. Skovbjerg (*) Department of Medical Biochemistry and Genetics, The Panum Institute, Blegdamsvej 3, 2200 Copenhagen N, Denmark e-mail: hsk@imbg.ku.dk Tel.: +45-353-27793 Fax: +45-353-67980

Adult-Onset Autoimmune Enteropathy in the Setting of Thymoma Successfully Treated with Infliximab

Autoimmune enteropathy (AIE) is characterized by chronic intractable diarrhea, weight loss from malabsorption, and immune-mediated damage to the intestinal mucosa. The syndrome initially was described in 1982 in a male child (1, 2). Walker-Smith formulated a set of diagnostic criteria for the disorder that remain in use: (a) small intestinal villous atrophy, (b) unresponsiveness to dietary restriction, and (c) circulating enterocyte antibodies and/or associated autoimmune conditions (3). AIE also occurs in the setting of immunoglobulin deficiencies, a known risk factor for the development of autoimmune disorders (4, 5). The first published cases of adult-onset AIE appeared in 1997 when Corazza et al. described two subjects aged 38 and 47 years with severe diarrhea and malabsorption, small bowel villous atrophy, no response to gluten-free diet, and circulating antienterocyte antibodies (6, 7). Only occasional case reports of adults with this disorder have appeared since, and similarly to pediatric cases, adultonset AIE has been associated with autoimmunity and immunoglobulin deficiency. AIE likely is but one manifestation of a more diffuse autoimmune disorder of the gastrointestinal system with heterogeneous manifestations including gastritis, colitis, hepatitis, and pancreatitis, as well as a variety of autoantibodies, such as anti–parietal cell antibodies and anti–goblet cell antibodies (4, 8, 9). Leon et al. recently coined the term generalized autoimmune gut disorder (GAGD) for those whose autoimmune gastrointestinal damage extends beyond the small intestine,

Questions and answers about the neurology of gluten sensitivity

In recent years there has been a plethora of articles claiming that various neurological syndromes are associated with or are caused by gluten sensitivity. However, the busy clinical neurologist needs to know the answers to just two main questions – does gluten sensitivity predispose patients to the development of various neurological complications, and should a patient with a cryptogenic neurological illness be investigated for occult gluten sensitivity (and if so how)? WHAT IS GLUTEN SENSITIVITY? Coeliac disease is a classic gluten sensitive enteropathy, typically presenting in childhood. It is common with a prevalence of between 1 : 80 and 1 : 300. There is characteristic small bowel villous atrophy (Fig. 1a) associated with abdominal pain, malabsorption and weight loss. A gluten-free diet rapidly reverses this atrophy (within weeks) (Fig. 1b), corrects malabsorption and leads to symptomatic improvement. In addition, patients may sometimes present with non-specific or trivial complaints and the diagnosis