The Lancet

Volume 343, Issue 8891, 22 January 1994, Pages 200203

Originally published as Volume 1, Issue 8891

Coeliac Disease in Year 2000: exploring the iceberg

  1. Catassi, MD , a, I-M. Rätsch, MDa, E. Fabiani, MDa, M. Rossini, MDa, Prof G.V. Coppa, MDa, Prof P.L. Giorgi, MDa, F. Bordicchia, MDb, F. Candela, PhDba Department of Pediatrics, University of Ancona , United Kingdomb Department of Clinical Chemistry, “G Salesi” Children’s Hospital Ancona, Italy


It is now generally believed that subclinical coeliac disease is common in the general population. We have undertaken screening for this disorder in a school district in central Italy. Screening was divided into three levels: first, IgG and IgA antigliadin antibody (AGA) assay on capillary blood obtained by finger prick; second, AGA plus IgA anti-endomysium antibody (AEA) test and measurement of serum immunoglobulins in venous blood; and third, intestinal biopsy. 3351 students (66% of the eligible population) aged 11-15 years attended first-level screening. 71 (2%) were recalled because of AGA positivity; 18 of these satisfied second-level criteria and underwent intestinal biopsy. Coeliac disease was diagnosed in 11 subjects, most of whom had no serious symptoms. Selective IgA deficiency was found in 4 subjects, 1 of whom also had coeliac disease. The prevalence of subclinical coeliac disease in the study group was 3 28 per 1000. Coeliac disease screening is feasible and involves only slight discomfort to the general population. Such screening can detect large numbers of cases of coeliac disease, which can be treated with a gluten-free diet. Many subclinical cases of coeliac disease would not be detected by screening only a selected group of at-risk patients.



Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines

Authors: Drago, Sandro1; El Asmar, Ramzi2; Di Pierro, Mariarosaria1; Grazia Clemente, Maria2; Sapone, Amit Tripathi Anna2; Thakar, Manjusha2; Iacono, Giuseppe3; Carroccio, Antonio3; D’Agate, Cinzia4; Not, Tarcisio5; Zampini, Lucia1; Catassi, Carlo1; Fasano, Alessio2

Source: Scandinavian Journal of Gastroenterology, Volume 41, Number 4, March 2006 , pp. 408-419(12)


Objective:  Little is known about the interaction of gliadin with intestinal epithelial cells and the mechanism(s) through which gliadin crosses the intestinal epithelial barrier. We investigated whether gliadin has any immediate effect on zonulin release and signaling. Material and methods. Both ex vivo human small intestines and intestinal cell monolayers were exposed to gliadin, and zonulin release and changes in paracellular permeability were monitored in the presence and absence of zonulin antagonism. Zonulin binding, cytoskeletal rearrangement, and zonula occludens-1 (ZO-1) redistribution were evaluated by immunofluorescence microscopy. Tight junction occludin and ZO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR). Results. When exposed to gliadin, zonulin receptor-positive IEC6 and Caco2 cells released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein–protein interaction, and increased monolayer permeability. Pretreatment with the zonulin antagonist FZI/0 blocked these changes without affecting zonulin release. When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. Conclusions. Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.



Scandinavian Journal of Gastroenterology

Dietary Analysis in Symptomatic Patients with Coeliac Disease on a Gluten-Free Diet: the Role of Trace Amounts of Gluten and Non-Gluten Food Intolerances

1999, Vol. 34, No. 8 , Pages 784-789 (doi:10.1080/003655299750025714)

  1. B. Faulkner-Hogg, W. S. Selby, R. H. Loblay

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Background: Whereas many people with coeliac disease (CD) are asymptomatic when consuming a gluten-free diet (GFD), a proportion continues to experience symptoms. The reasons for this are unclear. Methods: Thirty-nine adult members of The Coeliac Society of New South Wales, all of whom had persistent gastrointestinal symptoms despite adhering to a GFD, were evaluated. Dietary analysis indicated that 22 (56%) were consuming a GFD as defined by the WHO/FAO Codex Alimentarius (Codex-GFD), in which foods containing up to 0.3% of protein from gluten-containing grains can be labelled as `gluten free’. The remaining 17 were following a no detectable gluten diet (NDG)-GFD, as defined by Food Standards Australia. All subjects were required to follow a NDG-GFD during the study. Those in whom symptoms persisted after changing from a Codex-GFD and those who entered the study already on a NDG-GFD began an elimination diet followed by open and double-blind challenges to identify specific non-gluten food or food chemical intolerances. Results: Of 22 patients who switched to a NDG-GFD symptoms resolved in 5 (23%) and were reduced in 10 others (45%). Thirty-one subjects commenced the elimination diet. Symptomatic improvement was experienced in 24 (77%). Subsequent food or food chemical challenges resulted in a mean of five positive challenges per individual. Diarrhoea was the most commonly provoked symptom, followed by headache, nausea, and flatulence. Symptoms were especially provoked by amine, salicylate and soy. Conclusion: The consumption of trace amounts of gluten, traditionally allowed in a Codex-GFD, may be responsible for the continuing symptoms seen in some patients with CD. Further investigation for non-gluten food intolerances should follow if symptoms persist after adherence to a NDG-GFD.


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Recent advances in the formulation of gluten-free cereal-based products

E Gallaghera, , 1, , T.R Gormleya, E.K Arendtba Teagasc, The National Food Centre, Ashtown, Dublin 15, Ireland

b Department of Food and Nutritional Science, National University of Ireland, Cork, Ireland, How to Cite or Link Using DOI

Trends in Food Science & Technology

Volume 15, Issues 3–4, March–April 2004, Pages 143–152

NFIF Part 1


The replacement of gluten presents a major technological challenge, as it is an essential structure-building protein, which is necessary for formulating high quality cereal-based goods. Rising demands for gluten free products parallels the apparent or real increase in coeliac disease, or other allergic reactions/intolerances to gluten. This paper reviews the current prevalence of coeliac disease, and recent advances in the preparation of gluten-free products, using starches, hydrocolloids, gums and novel ingredients and processes.


Fig. 1. Iceberg model depicting prevalence of coeliac disease (Feighery, 1999).



Acta Paediatrica

Volume 85, Issue Supplement s412, pages 10–14, May 1996

Latent and potential coeliac disease

R Troncone*, L Greco, M Mayer, F Paparo, N Caputo, M Micillo, P Mugione, S Auricchio

Article first published online: 21 JAN 2008

DOI: 10.1111/j.1651-2227.1996.tb14240.x

Under the umbrella of coeliac disease (CD), or gluten-sensitive enteropathy, the concepts of silent, latent and potential CD have recently been introduced. While silent CD is marked by severe damage to the jejunal mucosa in the absence of clinical symptoms, both latent and potential CD are characterized by a jejunal mucosa that would be reported as normal by most clinical pathologists in an individual on a gluten-containing diet. As opposed to potential coeliac patients, latent subjects sometime in their life have had a flat jejunal biopsy which recovered on a gluten-free diet. Latent coeliac patients are often symptomatic; neither high titres of gliadin antibodies nor mucosal changes (including raised intraepithelial lymphocyte counts) are obligate features of latent CD, although the presence of elevated endomysial antibodies is probably the best predictor of progression towards villous atrophy. The term potential CD has been proposed for those subjects who do not have, and have never had, a jejunal biopsy consistent with overt CD, and yet have immunological abnormalities similar to those found in coeliac patients. Good markers of potential CD include the presence of serum endomysial antibodies, a high count of intraepithelial lymphocytes and subtle pathological alterations such as increased density of intraepithelial lymphocytes expressing γδ T cell receptor, signs of activated mucosal cell-mediated immunity, coeliac-like intestinal antibody pattern, and positive rectal gluten challenge.



Coeliac Disease, autoimmune diseases and gluten exposure

2005, Vol. 40, No. 4 , Pages 437-443 (doi:10.1080/00365520510012181)

Mervi Viljamaa1, 2, Katri Kaukinen1, 2, Heini Huhtala2, Sinikka Kyrönpalo3, Martin Rasmussen3 and Pekka Collin1, 2

1Departments of Internal Medicine and Gastroenterology, Tampere University Hospital, Tampere, Finland

2School of Public Health and Medical School, University of Tampere, Tampere, Finland

3Tampere Health Center, Tampere, Finland

Correspondence: Pekka, Collin, MD Medical School, University of Tampere, FIN-33014, Finland, +358 3 3116 7869, +358 3 2158 402

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Objective Gluten-free diet treatment has been proposed to prevent the development of autoimmune diseases in coeliac subjects. The aim here was to investigate the occurrence of autoimmune disorders in relation to gluten intake in coeliac patients in a well-defined area. Material and methods The frequency of autoimmune disorders was evaluated in 703 adults and children with coeliac disease and in 299 controls with normal duodenal histology. Incidence figures were given per 10,000 person-years. In logistic regression analysis, where the prevalence of autoimmune disorders was a dependent variable, the effect of age at end of follow-up, age at diagnosis of coeliac disease, actual gluten exposure time, gender and diagnostic delay were assessed. Results The prevalence of autoimmune diseases was significantly higher in coeliac subjects than in controls. In logistic regression analysis, age at end of follow-up, age at diagnosis of coeliac disease and female gender increased the risk of autoimmune disorders, whereas actual gluten exposure time reduced the risk; diagnostic delay had no effect. A similar, though not statistically significant, trend was seen in childhood coeliac disease to that in the whole study group. Conclusions Despite that fact that patients with coeliac disease are at increased risk of various autoimmune conditions, the duration of gluten exposure seems not to be of crucial importance in the development of autoimmune diseases.

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Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial

The American Journal of Gastroenterology 106, 508-514 (March 2011) | doi:10.1038/ajg.2010.487

Jessica R Biesiekierski, Evan D Newnham, Peter M Irving, Jacqueline S Barrett, Melissa Haines, James D Doecke, Susan J Shepherd, Jane G Muir and Peter R Gibson


Despite increased prescription of a gluten-free diet for gastrointestinal symptoms in individuals who do not have celiac disease, there is minimal evidence that suggests that gluten is a trigger. The aims of this study were to determine whether gluten ingestion can induce symptoms in non-celiac individuals and to examine the mechanism.


A double-blind, randomized, placebo-controlled rechallenge trial was undertaken in patients with irritable bowel syndrome in whom celiac disease was excluded and who were symptomatically controlled on a gluten-free diet. Participants received either gluten or placebo in the form of two bread slices plus one muffin per day with a gluten-free diet for up to 6 weeks. Symptoms were evaluated using a visual analog scale and markers of intestinal inflammation, injury, and immune activation were monitored.


A total of 34 patients (aged 29–59 years, 4 men) completed the study as per protocol. Overall, 56% had human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8. Adherence to diet and supplements was very high. Of 19 patients (68%) in the gluten group, 13 reported that symptoms were not adequately controlled compared with 6 of 15 (40%) on placebo (P=0.0001; generalized estimating equation). On a visual analog scale, patients were significantly worse with gluten within 1 week for overall symptoms (P=0.047), pain (P=0.016), bloating (P=0.031), satisfaction with stool consistency (P=0.024), and tiredness (P=0.001). Anti-gliadin antibodies were not induced. There were no significant changes in fecal lactoferrin, levels of celiac antibodies, highly sensitive C-reactive protein, or intestinal permeability. There were no differences in any end point in individuals with or without DQ2/DQ8.


“Non-celiac gluten intolerance” may exist, but no clues to the mechanism were elucidated.



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

A Sbarbatia, , E Vallettab, M Bertinib, M Cipollic, M Morronid, L Pinellib, L Tatòb

a Section of Anatomy and Histology, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy

b Department of Pediatrics, University Hospital, Verona, Italy

c Cystic Fibrosis Center, Ospedale Civile Maggiore, Verona, Italy

d Institute of Normal Human Morphology, University Hospital, Ancona, Italy, How to Cite or Link Using DOI


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.




The gluten syndrome: A neurological disease

Rodney Philip Kinvig Ford,

The Children’s Gastroenterology and Allergy Clinic, P.O. Box 25-265, Christchurch 8144, New Zealand, How to Cite or Link Using DOI


Hypothesis: Gluten causes symptoms, in both celiac disease and non-celiac gluten-sensitivity, by its adverse actions on the nervous system.

Many celiac patients experience neurological symptoms, frequently associated with malfunction of the autonomic nervous system. These neurological symptoms can present in celiac patients who are well nourished. The crucial point, however, is that gluten-sensitivity can also be associated with neurological symptoms in patients who do not have any mucosal gut damage (that is, without celiac disease).

Gluten can cause neurological harm through a combination of cross reacting antibodies, immune complex disease and direct toxicity. These nervous system affects include: dysregulation of the autonomic nervous system, cerebella ataxia, hypotonia, developmental delay, learning disorders, depression, migraine, and headache.



Prevalence of celiac disease in dyspeptic patients


Prevalência de doença celíaca em pacientes dispépticos

Vinícius Machado de LimaI; Lenora GandolfiII; José Augusto de Araújo PiresI; Riccardo PratesiII

IGastroenterology Unit Dept. of Internal Medicine and

IIDept. of Pediatrics, Brasilia School of Medicine, University of Brasilia, DF, Brazil


BACKGROUND: Celiac disease is one of the most common dietary-mediated inflammatory enteropathies that occur in genetically predisposed individuals in response to gluten intolerance. This disorder has become more common than in the past, even if it frequently remains undetected for long periods of time. The screening of patients with dyspepsia, a symptom that can be a manifestation of celiac disease, may allow an early identification of affected individuals. Endoscopy and serological tests may have an important role in the management of these patients.

AIMS: Determining the prevalence of celiac disease in dyspeptic patients submitted to routine diagnostic upper gastrointestinal endoscopy.

PATIENTS/METHODS: Endoscopic findings, duodenal biopsy histological specimens and serological test results were assessed and compared in 142 patients consecutively admitted with dyspeptic symptoms between October 2001 and October 2003.

RESULTS: An endoscopic pattern suggestive of celiac disease was observed in four patients. The IgG-AGA assay was positive in 24 patients. Two of the IgG-AGA positive patients also yielded positive results on the IgA-EMA test and concomitantly disclosed endoscopic pattern and histological features in duodenal biopsy compatible with celiac disease. Abnormal endoscopic findings were notably marked in biopsy proven celiac patients. Therefore, a 1.4% prevalence of celiac disease was observed in this study group.

CONCLUSIONS: The high prevalence of celiac among dyspeptic symptomatic individuals indicates that they are a higher risk group for developing celiac disease. Undiagnosed celiac disease may be inferred by endoscopic markers of duodenal villous atrophy. Endoscopic findings, however, may be inadequate to suitably diagnose this disease and consequently the incorporation of diagnostic serologic assays of celiac disease in routine testing for dyspepsia is strongly recommended.



Cutting-Edge Issues in Celiac Disease and in Gluten Intolerance

  1. Bizzaro, R. Tozzoli, D. Villalta, M. Fabris and E. Tonutti

From the issue entitled “Allergies, Autoimmunity and the GI tract”


Celiac disease (CD) is a gluten-dependent immune-mediated disease with a prevalence in the general population estimated between 0.3% and 1.2%. Large-scale epidemiological studies have shown that only 10–20% of cases of CD are identified on the basis of clinical findings and that laboratory tests are crucial to identify subjects with subtle or atypical symptoms. The correct choice and clinical use of these diagnostic tools may enable accurate diagnosis and early recognition of silent CD cases. In this review, we have considered some relevant aspects related to the laboratory diagnosis of CD and, more extensively, of gluten intolerance, such as the best combination of tests for early and accurate diagnosis, the diagnostic role of new tests for detecting antibodies against neoepitopes produced by the transglutaminase–gliadin complex, the forms of non-celiac gluten intolerance (gluten sensitivity), and the use and significance of measuring cytokines in CD.




Elena F Verdu, David Armstrong and Joseph A Murray

Between Celiac Disease and Irritable Bowel Syndrome: The “No Man’s Land” of Gluten Sensitivity Gluten sensitivity and IBS

The American Journal of Gastroenterology 104, 1587-1594 (June 2009) | doi:10.1038/ajg.2009.188


The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.



Celiac Disease Pathogenesis: The Proinflammatory Cytokine Network

Journal of Pediatric Gastroenterology & Nutrition:

August 2008 – Volume 47 – Issue – p S27-S32

doi: 10.1097/MPG.0b013e3181818fb9

Original Articles

Garrote, José Antonio*,†; Gómez-González, Emma*; Bernardo, David*; Arranz, Eduardo*; Chirdo, Fernando‡

In susceptible individuals, the adaptive response, mediated by the activation of antigen-specific T lymphocytes, drives a proinflammatory response, which ends in an immune-mediated enteropathy characterized by villous atrophy, crypt hyperplasia, and recruitment of intraepithelial lymphocytes. In addition, some gluten peptides are able to induce an innate immune response in intestinal mucosa. The molecular mechanisms and the cells involved in the initial stages of the gluten-intestinal mucosa interaction are poorly understood to date. There is evidence of a direct toxic effect of gluten peptides in several biological models. However, the failure to control the inflammatory response may be one of the factors underlying gluten intolerance in these individuals. The cytokine network involved in celiac disease is characterized by abundant interferon-γ in the intestinal mucosa. In addition, the production of interleukin (IL)-15, IL-18, and IL-21 is linked to gluten intake, which can drive the inflammatory response probably sustained by IL-18, IL-21, and perhaps IL-27 through STAT1 and STAT5 pathways, whereas neither IL-12 nor IL-23 plays a significant role in pathogenic mechanisms. Herein we describe the involvement of these activation pathways in the context of the pathogenesis of celiac disease.



International Archives of Allergy and Immunology 2003, Vol. 132, No. 2

Pathomechanisms in Celiac Disease

Dieterich W, Esslinger B, Schuppan D

Int Arch Allergy Immunol 2003;132:98–108 (DOI: 10.1159/000073710)


Celiac disease is a complex autoimmune disease which is characterized by a strong genetic association (HLA-DQ2 or -DQ8), gluten as nutritional etiological factor, and the enzyme tissue transglutaminase as endomysial autoantigen. Patients develop highly predictive IgA autoantibodies to tTG. Certain gluten peptides are presented by the disease-associated HLA-DQ2/DQ8 molecules leading to stimulation of gluten-specific T cells. This immune response which is driven in the lamina propria causes the mucosal transformation characteristic for celiac disease. Increased intestinal expression of tTG in patients with CD appears to play an important role in the pathogenesis of CD. Thus, modification of gluten peptides by tTG, especially deamidation of certain glutamine residues, can enhance their binding to HLA-DQ2 or -DQ8 and potentiate T cell stimulation. Furthermore, tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa. New therapeutic approaches aim at proteolytic destruction of immunodominant gliadin peptides that are resistant to intestinal enzymes by bacterial prolyl endopeptidases, the inhibition of tTG activity with highly specific enzyme inhibitors or at HLA-DQ2/DQ8 blocking peptide analogues.



Prevalence of celiac disease in multiple sclerosis

Luis Rodrigo1*, Carlos Hernández-Lahoz2, Dolores Fuentes1, Noemí Alvarez1, Antonio López-Vázquez3 and Segundo González3



Celiac disease (CD) is a common systemic disease related to a permanent intolerance to gluten and is often associated with different autoimmune and neurological diseases. Its mean prevalence in the general population is 1-2% worldwide. Our aim was to study the prevalence of celiac disease in a prospective series of Multiple Sclerosis (MS) patients and their first-degree relatives.


We analyzed the prevalence of serological, histological and genetic CD markers in a series of 72 MS patients and in their 126 first-degree relatives, compared to 123 healthy controls.


Tissue IgA-anti-transglutaminase-2 antibodies were positive in 7 MS patients (10%), compared to 3 healthy controls (2.4%) (p < 0.05). OR: 5.33 (CI-95%: 1.074-26.425). No differences were found in HLA-DQ2 markers between MS patients (29%) and controls (26%) (NS).

We detected mild or moderate villous atrophy (Marsh III type) in duodenal biopsies, in 8 MS patients (11.1%). We also found a high proportion of CD among first-degree relatives: 23/126 (32%). Several associated diseases were detected, mainly dermatitis 41 (57%) and iron deficiency anemia in 28 (39%) MS patients. We also found in them, an increased frequency of circulating auto-antibodies such as anti-TPO in 19 (26%), ANA in 11 (15%) and AMA in 2 (3%).


We have found an increased prevalence of CD in 8 of the 72 MS patients (11.1%) and also in their first-degree relatives (23/126 [32%]). Therefore, increased efforts aimed at the early detection and dietary treatment of CD, among antibody-positive MS patients, are advisable.


Journal of Pediatric Hematology/Oncology:

June 2006 – Volume 28 – Issue 6 – pp 346-349

Original Articles

Celiac Disease and Childhood Cancer

Cereda, Stefano MD; Cefalo, Graziella MD; Spreafico, Filippo MD; Catania, Serena MD; Meazza, Cristina MD; Podda, Marta MD; Terenziani, Monica MD


Celiac disease is an autoimmune enteropathy developing in genetically predisposed individuals after mucosal contact with gluten, secondary to unknown triggering factors. An increased rate of malignancies in adults with celiac disease has been confirmed in several studies, but there is considerable evidence that a gluten-free diet protects against the development of cancer. The association between celiac disease and childhood cancer is not clear. Few cases are reported in the literature. Here, we report the cases referred to our pediatric oncology unit with a review of the literature.



Food Choice as a Key Management Strategy for Functional Gastrointestinal Symptoms

The American Journal of Gastroenterology 107, 657-666 (May 2012) | doi:10.1038/ajg.2012.49

Peter R Gibson and Susan J Shepherd


Recognition of food components that induce functional gut symptoms in patient’s functional bowel disorders (FBD) has been challenging. Food directly or indirectly provides considerable afferent input into the enteric nervous system. There is an altered relationship between the afferent input and perception/efferent response in FBD. Defining the nature of food-related stimuli may provide a means of minimizing such an input and gut symptoms. Using this premise, reducing the intake of FODMAPs (fermentable oligo-, di-, and mono-saccharides and polyols)—poorly absorbed short-chain carbohydrates that, by virtue of their small molecular size and rapid fermentability, will distend the intestinal lumen with liquid and gas—improves symptoms in the majority of patients. Well-developed methodologies to deliver the diet via dietician-led education are available. Another abundant source of afferent input is natural and added food chemicals (such as salicylates, amines, and glutamates). Studies are needed to assess the efficacy of the low food chemical dietary approach. A recent placebo-controlled trial of FODMAP-poor gluten provided the first valid evidence that non-celiac gluten intolerance might actually exist, but its prevalence and underlying mechanisms require elucidation. Food choice via the low FODMAP and potentially other dietary strategies is now a realistic and efficacious therapeutic approach for functional gut symptoms.



Gastroenterology and Hepatology From Bed to Bench ©2012 RIGLD, Research Institute for Gastroenterology and Liver Diseases

Home > Vol 5, No 1 (2012) > Rostami Nejad

Gluten related disorders

Mohammad Rostami Nejad, Maryam Karkhane, Abdolrazagh Marzban, Ehsan Nazemalhosseini Mojarad, Kamran Rostami


Gluten associated disorders and the question around these associations has recently attracted attentions of many health professionals. This is because of high prevalence of undiagnosed gluten related disorders presenting with a multitude of symptoms and complications inside and outside small bowel. While the environmental factors associated with a complex genetics are leading to destructions of the small intestinal villi resulting in malabsorption syndrome in CD, GS is characterised by negative antibodies and grossly normal histology. The association between celiac disease and other disorders has been clearly established and there have been many reports of numerous intestinal and extra intestinal coexistent disorders with CD. But there is little information available regarding the clinical behavior of gluten sensitivity. In this review we discuss the clinical presentation of non-celiac GS and the prospect of current and the future diagnostic pathway.



Gastroenterology and Hepatology From Bed to Bench. 2011;4(3): 102-108

©2011 RIGLD, Research Institute for Gastroenterology and Liver Diseases

Subclinical celiac disease and gluten sensitivity

Mohammad Rostami Nejad1, Sabine Hogg- Kollars2, Sauid Ishaq3, Kamran Rostami2, 3

1Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2School of Immunity and Infection, University of Birmingham, UK

3Dudley Group of Hospital NHS Foundation Trust, UK


Atypical presentation is the most common form of celiac disease (CD). Although the terminologies like latent, silent and potential have expressed different aspects of clinical and pathological behavior of CD, they also have contributed in some extent to confusion between clinicians and patients due to the multiple definitions and uncertainty around them. In the light of new advances and the discovery of entities such as non-celiac gluten sensitivity, using subclinical instead of silent and atypical instead of potential/latent may simplify the understanding behind the clinical behavior of atypical CD. The evidence behind a lower threshold for considering a gluten free diet (GFD) in non-celiac gluten sensitive patients would strongly support adjusting the terminologies to treatable clinicopathological conditions. Keywords: Subclinical, Celiac disease, Atypical, Microscopic enteritis, Gluten sensitivity.



New understanding of gluten sensitivity

Nature Reviews Gastroenterology and Hepatology 9, 295-299 (May 2012) | doi:10.1038/nrgastro.2012.15

Umberto Volta & Roberto De Giorgio


Among gluten-related disorders, gluten sensitivity is an emerging entity that is characterized by a wide array of manifestations. In particular, patients complain of IBS-like symptoms and extraintestinal manifestations that occur shortly after the ingestion of gluten. Symptoms improve or disappear when gluten is withdrawn from the diet, and recur if gluten is reintroduced. Laboratory tests are usually unhelpful for diagnosis, although ~50% of patients are positive for IgG antigliadin antibodies. The natural history of gluten sensitivity is unknown; in particular, it is still to be clarified whether this disorder is permanent or transient and whether it is linked to autoimmunity. The pathogenesis of gluten sensitivity is unclear; data so far demonstrate a predominant activation of innate immune responses. Further research is necessary to establish the main clinicopathological features of gluten sensitivity, thus enabling physicians to improve their management of the increasing number of patients who are sensitive to dietary gluten.



Clinical & Experimental Immunology

Volume 133, Issue 1, pages 139–143, July 2003


Gliadin, endomysial and thyroid antibodies in patients with latent autoimmune diabetes of adults (LADA)

  1. KUČERA1,*,
  4. NOVÁK2,
  6. ANDĚL2

Article first published online: 24 JUN 2003

DOI: 10.1046/j.1365-2249.2003.02205.x



anti-gliadin;coeliac;latent autoimmune diabetes of adults;thyroidal


Latent autoimmune diabetes of adults (LADA) manifested after the age of 35 is characterized by the presence of disease-specific autoantibodies (anti-glutamate decarboxylase GADAb, anti-IA2Ab). However, autoimmunity in Type 1 diabetes mellitus is not targeted only to pancreatic beta-cells. No data have so far been published concerning the antibodies associated with other autoimmune disease in LADA patients. The presence of anti-thyroglobulin (TGAb), anti-thyroid peroxidase (TPOAb), anti-gliadin IgA (AGAAb) and IgG (AGGAb) and endomysial antibodies (EMAb) in sera of 68 diabetics typed as LADA was compared with the antibody presence in sera of 85 patients with Type 2 diabetes. We found a significantly higher occurrence of gliadin antibodies in LADA patients: the rate of AGGAb was 19·1% in comparison with 3·5% in the T2DM group (P = 0·0026), the rate of AGAAb was 13·2% in comparison with 3·5% (P = 0·035). The prevalence of EMAb was very low in both groups (1·5% and 0). The two groups differed significantly in the TPOAb rate: 22·1% in LADA compared to 9·4% in T2DM (P = 0·04), whereas no significant difference was found in the presence of TGAb (8·8% and 3·5%, P = 0·187). In comparison with T2DM patients, LADA patients were found to express higher antibody activity against gluten-related antigens and against TPO.



American Diabetes Association

doi: 10.2337/diacare.24.1.27

Diabetes Care January 2001 vol. 24 no. 1 27-32

Comparative Analysis of Organ-Specific Autoantibodies and Celiac Disease—Associated Antibodies in Type 1 Diabetic Patients, Their First-Degree Relatives, and Healthy Control Subjects

Clemens Jaeger, MD, Erifili Hatziagelaki, MD, Rüdiger Petzoldt, MD, PHD and Reinhard G. Bretzel, MD, PHD

+ Author Affiliations

From the Third Medical Department and Policlinic (C.J., E.H., R.G.B.), Justus-Liebig-University, Giessen; and the Diabetes Center at Bad Oeynhausen (R.P.), University of Bochum, Bochum, Germany.

Address correspondence and reprint requests to Clemens Jaeger, MD, Third Medical Department and Policlinic, Justus-Liebig-University, Rodthohl 6, 35385, Giessen, Germany.


OBJECTIVE— In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders.

RESEARCH DESIGN AND METHODS— In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay).

RESULTS— The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes—associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recent-onset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive—specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05).


CONCLUSIONS— We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre—type 1 diabetes.


Abbreviations: APS, autoimmune polyendocrine syndrome; ELISA, enzyme-linked immunosorbent assay; GADA, GAD65 antibodies; GPC, gastric parietal cell; IAA, insulin autoantibodies; ICA, islet cell antibodies; TG, thyroglobulin; TPO, thyroid peroxidase; tTGC, tissue transglutaminase C; WHO, World Health Organization.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Accepted October 3, 2000.

Received July 25, 2000.

by the American Diabetes Association, Inc.



The Journal of Pediatrics

Volume 137, Issue 2 , Pages 263-265, August 2000

Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease☆

Alessandro Ventura, MD, Elena Neri, MD, Claudio Ughi, MD, Agnese Leopaldi, Angello Città, Tarcisio Not, MD

Clinica Pediatrica e Laboratorio di Analisi, IRCCS “Burlo Garofolo” Trieste, Trieste, Italy; and Dipartimento de Pediatria, University of Pisa, Pisa, Italy

Received 26 August 1999; received in revised form 20 January 2000; accepted 8 March 2000.


Patients with celiac disease are at high risk of having autoimmune disorders. Moreover, untreated patients with celiac disease have been found to have a higher than expected prevalence of organ-specific autoantibodies. In a prospective study of 90 patients with celiac disease, we found that the prevalence of diabetes and thyroid-related serum antibodies was 11.1% and 14.4%, respectively. Like antiendomysium autoantibodies, these organ-specific antibodies seem to be gluten-dependent and tend to disappear during a gluten-free diet. (J Pediatr 2000;137:263-5)



IgA Antigliadin Antibodies as a Screening Method for Nonovert Celiac Disease in Children with Insulin-Dependent Diabetes Mellitus

Journal of Pediatric Gastroenterology & Nutrition:

July 1996 – Volume 23 – Issue 1 – pp 29-33

Original Article


Calero, P.; Ribes-Koninckx, C.*; Albiach, V.; Carles, C.; Ferrer, J.*



Summary: One hundred forty-one children with insulin dependent diabetes mellitus were screened for serum immunoglobulin A (IgA) antigliadin antibodies by means of an enzyme-linked immunosorbent assay (ELISA) method. None of them had gastrointestinal symptoms, and no major nutritional disturbances were detected except for a girl with moderate growth delay. Twelve patients with positive IgA antigliadin antibodies on two or more consecutive measurements underwent a small intestinal biopsy; four of them had a subtotal villous atrophy, and celiac disease was diagnosed; in another patient, a partial villous atrophy was observed. Children suffering from both diabetes and celiac disease showed an onset of diabetes at a younger age than did non-celiac patients. Prevalence of celiac disease in the screened population is 2.85%, which is higher than in the general population of the Comunidad Valenciana (one in 2,500 live births).



Autoimmune thyroid disorders and coeliac disease

Eur J Endocrinol February 1, 1994 130 137-140

Pekka Collin, Jorma Salmi, Olavi Hällström, Timo Reunala and Amos Pasternack


Collin P, Salmi J, Hällström O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol 1994;130:137–40. ISSN 0804–4643.

Eighty-three patients with autoimmune thyroid disorders were screened for coeliac disease. The screening was performed with IgA-class reticulin and endomysium antibody, IgA- and IgG-class gliadin antibody tests, and various biochemical tests for malabsorption. None of the tested subjects had selective IgA deficiency, which excludes the possibility of not detecting positives by an IgA-class test. Of the 83 patients, three asymptomatic coeliac patients were found, and one patient with coeliac disease previously diagnosed, an overall frequency of 4.8%. In addition, 25 patients with a solitary nodule of the thyroid gland were examined and one of them (4%) was found to have coeliac disease. By contrast, one (0.4%) out of 249 age- and sex-matched blood donors was found to have coeliac disease. All newly detected coeliac patients had IgA-class gliadin, reticulin and endomysium antibodies, but none of the patients had any gastrointestinal symptoms or abnormal biochemical findings suggesting coeliac disease. Treatment of thyroid disorders and coeliac disease was successful in these patients. The present results confirm that the frequency of subclinical coeliac disease is increased among patients with autoimmune thyroid disorders. IgA-class reticulin, endomysium or gliadin antibody tests are suitable screening methods for detecting these patients, as far as selective IgA-deficiency is excluded.

Pekka Collin, Department of Clinical Sciences, University of Tampere, PO Box 607, SF-33101 Tampere, Finland





Frequency and Significance of Anti-gliadin and Anti-endomysial Antibodies in Autoimmune Hepatitis

  1. Volta, L. De Franceschi, N. Molinaro, F. Cassani, L. Muratori, M. Lenzi, F. B. Bianchi and A. J. Czaja


Volume 43, Number 10 (1998), 2190-2195, DOI: 10.1023/A:1026650118759


Celiac disease has been associated with autoimmune disorders, but its frequency in autoimmune hepatitis is unknown. Sera from 157 patients with type1 autoimmune hepatitis, 24 patients with type 2autoimmune hepatitis, 62 patients with primary biliarycirrhosis, 30 patients with chronic hepatitis B, and 80patients with chronic hepatitis C were tested forimmunoglobulin A anti-endomysial antibodies by indirect immunofluorescence and immunoglobulin A and Gantibodies to gliadin by enzyme immunoassay. Duodenalbiopsy evaluation was recommended in patientsseropositive for immunoglobulin A anti-endomysialantibodies. Immunoglobulin A anti-endomysial antibodieswere present in eight of the 181 patients with autoimmune hepatitis (4%), including six with type 1disease (4%) and two with type 2 disease (8%). Immunoglobulin A antibodies to gliadin were found in six of these eight patients, but they were also present in two others, including one patient with chronic hepatitis C. Five of the eight patients with immunoglobulin A antiendomysial antibodies, including three patients with no gastrointestinal symptoms, had duodenalbiopsies and subtotal villous atrophy was present in all of them. No patient with primary biliary cirrhosis or chronic viral hepatitis had antiendomysialantibodies. The presence of celiac disease in autoimmune hepatitis is high (at least one in 36 patients) and it is predominantly asymptomatic. Screening with anti-endomysial and anti-gliadin antibodies should be performed and results confirmed with intestinal biopsy.






High prevalence of coeliac disease in Danish children with type I diabetes mellitus

D Hansen1, FN Bennedbæk2, LK Hansen1,*, M Høier-Madsen3, L Hegedüs2, BB Jacobsen1, S Husby1

Article first published online: 2 JAN 2007

DOI: 10.1111/j.1651-2227.2001.tb01568.x

Acta Paediatrica :Volume 90, Issue 11, pages 1238–1243, November 2001


Children;coeliac disease;tissue transglutaminase antibodies;type I diabetes mellitus

The purpose of this population-based study was to determine the prevalence of coeliac disease (CD) in 106 Danish children (age 2-18 y) with type I diabetes mellitus compared with 106 age-and sex-matched healthy controls. Serum samples were analysed for immunoglobulin A (IgA) and IgG gliadin antibodies by enzyme-linked immunosorbent assay (ELISA), for IgA endomysium antibodies (EMA) by immunofluorescence and for IgA tissue transglutaminase antibodies (tTGA) by ELISA. None of the controls had EMA or tTGA. Two diabetics previously diagnosed with CD were antibody negative on a gluten-free diet. Ten diabetics had both EMA and tTGA. Intestinal biopsy was performed in nine of them. All biopsies showed a histological picture of partial or total villous atrophy confirming the diagnosis of CD. Diabetics with CD were significantly younger (p= 0.026), had an earlier onset of diabetes (p= 0.005), had a lower height standard deviation score (p= 0.019) and more often had thyroid antibodies (p= 0.040) compared with diabetics without CD.

Conclusion: A high prevalence of CD of 10.4% (95% confidence interval 4.6–16.2%) was found in young Danish diabetics. Early onset of diabetes may predispose to CD. Routine serological screening for CD may be valuable in patients with type I diabetes mellitus.



Prevalence and early diagnosis of coeliac disease in autoimmune thyroid disorders.


Cuoco L, Certo M, Jorizzo RA, De Vitis I, Tursi A, Papa A, De Marinis L, Fedeli P, Fedeli G, Gasbarrini G

Department of Internal Medicine, Catholic University S.C., Rome, Italy.

Italian Journal of Gastroenterology and Hepatology [1999, 31(4):283-287]

BACKGROUND AND AIMS: Coeliac disease is associated with several autoimmune disorders such as insulin-dependent diabetes, Sjogren’s syndrome, Addison’s disease and thyroid diseases. The aim of our study was to evaluate the prevalence of coeliac disease in patients affected by autoimmune thyroid diseases by means of anti-gliadin and anti-endomysial antibodies. PATIENTS: We studied 92 patients affected by autoimmune thyroid diseases (47 chronic autoimmune thyroiditis, 22 Hashimoto’s thyroiditis and 23 Graves’ disease). Ninety patients with non-autoimmune thyroid disorders (51 multifollicular goitre, 28 solitary nodule and 11 papillary carcinoma) and 236 blood donors also took part in the study as control groups. METHODS: Total serum IgA were measured in all subjects to exclude selective IgA deficiency; then we measured anti-gliadin antibodies and anti-endomysial antibodies. In patients with anti-gliadin/anti-endomysial antibody positivity and/or with haematinic and laboratory signs of malabsorption we carried out gastrointestinal endoscopy with duodenal histological examination. RESULTS: Among the 92 patients with autoimmune thyroid disease, 4 (4.3%) showed anti-gliadin and anti-endomysial positivity and had coeliac disease; among the 90 patients with non autoimmune thyroid diseases, 1 (1.1%) had coeliac disease; finally, among the blood donors, 1 subject (0.4%) was anti-gliadin-anti-endomysium antibody positive and had coeliac disease. Those subjects presenting with only anti-gliadin antibody positivity did not have coeliac disease.

CONCLUSIONS: These results show that the prevalence of coeliac disease in patients with autoimmune thyroid diseases is significantly increased when compared with the general population (p = 0.009) but not with patients affected by non autoimmune thyroid disorders (p = 0.18). We suggest a serological screening for coeliac disease in all patients with autoimmune thyroid disease measuring anti-endomysial antibodies, considering that early detection and treatment of coeliac disease are effective in preventing its complications.



Genetic Modifications to Wheat


Among the changes introduced into wheat by geneticists:

–Enrichment in the glia-alpha-9 genetic sequence that provokes celiac disease. Nearly absent from the wheat of 1950, nearly all modern semi-dwarf wheat contains this genetic sequence. Is it any wonder why the incidence of celiac disease has quadrupled?

–Gliadin is a more powerful opiate–The changes introduced into the gliadin gene/protein make it a more potent opiate. While the digestive byproducts of gliadin bind to the opiate receptors of the brain, they lack the pain-relieving and euphoric effects of heroin and morphine, but “only” provoke addictive eating behavior and appetite stimulation. People who consume wheat consume, on average, 440 more calories per day, 365 days per year.

–Changes in the lectin unique to wheat, wheat germ agglutinin, that is responsible for 1) direct intestinal damamge, and 2) a Trojan horse effect of helping foreign substances gain entry into the bloodstream. This is likely at least part of the reason why wheat-eaters experience more lupus, rheumatoid arthritis, polymyositis, type 1 diabetes in children, worse ulcerative colitis and Crohns, more Hashimoto’s thyroiditis: Foreign proteins gain entry to the various organs of the body and result in “autoinflammation.” Changes in wheat lectin may have also led to more effective blocking of the hormone of satiety, leptin.

–Changes in alpha amylase inhibitors–These are the most common sources of wheat allergies, e.g., wheat allergy in kids.



Semin Gastrointest Dis. 2002 Oct;13(4):232-44.

Celiac sprue.

Cárdenas AKelly CP.


Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.


Celiac sprue, celiac disease, or gluten-sensitive enteropathy, is a malabsorption disorder of the small intestine that occurs after ingestion of wheat gluten in genetically susceptible individuals. This disease is characterized by intestinal malabsorption associated with villous atrophy of the small intestinal mucosa, clinical and histological improvement after adherence to strict gluten free diet, and relapse when gluten is reintroduced. Celiac sprue has a high prevalence in Western Europe and North America where it is estimated to affect 1:120 to 1:300 individuals. The pathogenesis of celiac sprue is related to inappropriate intestinal T-cell activation in HLA-DQ2 positive individuals triggered by antigenic peptides from wheat glutenor prolamins from barley and rye. Although previously thought to be mainly a disease of childhood onset, the diagnosis is increasingly being made in adults. There are a wide variety of presentations, which range from asymptomatic forms to severe diarrhea, weight loss and nutritional deficiencies. Extraintestinal manifestations including anemia, osteopenia or neurological disorders and associated conditions such as diabetes or hypothyroidism are commonly present. The availability of highly sensitive and specific serologic markers has dramatically facilitated the diagnosis of celiac sprue. However, the demonstration of characteristic histological abnormalities in a biopsy specimen of the small intestine remains the mainstay of diagnosis. Treatment consists of life-long avoidance of dietary gluten to control symptoms and to prevent both immediate and long-term complications.

PMID:  12462708



Diabetes Educ. 2013 May 14. [Epub ahead of print]

Celiac Disease in Patients With Type 1 Diabetes: Screening and Diagnostic Practices.

Simpson SMCiaccio EJCase SJaffe NMahadov SLebwohl BGreen PH.


Celiac Disease Center at Columbia University, New York, New York (Ms Simpson, Mr Ciaccio, Dr Mahadev, Dr Lebwohl, Dr Green).


ObjectiveThe purpose of this study was to investigate screening practices for celiac disease in patients with type 1 diabetes across North America. The research question investigated was whether diabetes centers screen for celiac disease in type 1 diabetes more frequently than other facilities. Research Design and Methods A survey with 27 questions on screening practices for celiac disease in patients with type 1 diabetes was designed by experts in celiac disease and diabetes. Surveys were sent by email to diabetes educators and dietitians throughout the United States and Canada between December 2010 and May 2011.ResultsThere were 514 respondents from 484 endocrine clinics, diabetes clinics, private practices, community nutrition centers, and inpatient centers. Thirty-five percent of work locations screened for celiac disease, with endocrine clinics reporting screening at the highest frequency (80%). Tissue transglutaminase was the most common screening test used. The most frequently recommended treatment of confirmed celiac disease was a gluten-free diet. However, only 71% of respondents recommended biopsy in patients with positive serologies. Most respondents (55.3%) reported that the gluten-free diet resulted in symptom improvement in the majority of patients.  Conclusions: Staff at endocrine clinics were more likely to suggest screening for celiac disease in patients with type 1 diabetes. Both low screening frequency as well as inconsistency in management of positive celiac disease serological tests indicated an increase in education regarding celiac disease in patients with type 1 diabetes is required. In addition uniform guidelines should be developed.







BMJ Case Rep. 2012 Jun 21;2012. pii: bcr0220125878. doi: 10.1136/bcr.02.2012.5878.

Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus.

Sildorf SMFredheim SSvensson JBuschard K.


Paediatric Unit, Copenhagen University Hospital, Herlev, Denmark.


A 5-year and 10-month old boy was diagnosed with classical type 1 diabetes mellitus (T1DM) without celiac disease. He started on a gluten-free diet after 2-3 week without need of insulin treatment. At the initiation of gluten-free diet, HbA1c was 7.8% and was stabilised at 5.8%-6.0% without insulin therapy. Fasting blood glucose was maintained at 4.0-5.0 mmol/l. At 16 months after diagnosis the fasting blood glucose was 4.1 mmol/l and after 20 months he is still without daily insulin therapy. There was no alteration in glutamic acid decarboxylase positivity. The gluten-free diet was safe and without side effects. The authors propose that the gluten-free diet has prolonged remission in this patient with T1DM and that further trials are indicated.





J Clin Endocrinol Metab. 2003 Jan;88(1):162-5.

Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes.

Pastore MRBazzigaluppi EBelloni CArcovio CBonifacio EBosi E.


Internal Medicine, Diabetes and Endocrinology Unit, San Raffaele Vita-Salute University Hospital and Scientific Institute, 20132 Milan, Italy.


Removal of gluten from the diet can attenuate the intensity of autoimmunity and reduces the incidence of diabetes in the non-obese diabetic mouse. In this study, we tested whether a gluten-free diet could reduce autoimmunity in human preclinical type 1 diabetes. A trial consisting of 6 months of a gluten-free diet followed by another 6 months of normal gluten-containing diet was performed in 17 first-degree relatives with at least 2 antibodies among islet cell antibodies, glutamic acid decarboxylase autoantibodies, protein tyrosine islet antigen-2 autoantibodies, and insulin autoantibodies. Treatment effect was measured as autoantibody titers and acute insulin response to iv glucose tolerance test. Two subjects dropped out for lack of compliance to diet restrictions. Of the remaining 15 subjects, 3 developed diabetes. Autoantibody titers did not show significant changes after 6 months of gluten-free diet and again after return to normal diet. Acute insulin response to iv glucose tolerance test significantly increased in 12 of 14 subjects after the first 6 months of gluten deprivation (P = 0.04) and decreased in 10 of 13 subjects during the following 6-month period of normal diet (P = 0.07). Insulin sensitivity (homeostasis model assessment-insulin resistance) nonsignificantly improved after the gluten-free diet and subsequently decreased (P < 0.005) after 6 months of normal diet. These findings indicate that 6 months of gluten deprivation do not influence humoral autoimmunity, but may have a beneficial effect on preservation of beta-cell function in subjects at risk for type 1 diabetes.



Bone. 2008 Aug;43(2):322-6. doi: 10.1016/j.bone.2008.04.004. Epub 2008 Apr 18.

The influence of gluten free diet on quantitative ultrasound of proximal phalanxes in children and adolescents with type 1 diabetes mellitus and celiac disease.

Valerio GSpadaro RIafusco DLombardi FDel Puente AEsposito ADe Terlizzi FPrisco FTroncone RFranzese A.


School of Movement Sciences (DiSiST), Parthenope University, Naples, Italy.


A reduced bone mineral density has been reported in patients with untreated celiac disease (CD) as well as in patients with poorly controlled type 1diabetes mellitus (T1DM). The aim of this study was to evaluate the bone mineral status by phalangeal quantitative ultrasound in 52 children and adolescents with both diseases (mean age 13.3+/-4.9 years). As a control group 50 patients with T1DM and no CD (age 12.2+/-4.0 years) were studied. The following bone parameters, amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were considered and expressed as z score. Compliance to gluten free diet and long term glycemic control (mean of four determinations of HbA1c in the last year) were also assessed. The lowest mean AD-SoS z score values were found in patients with T1DM and CD, who reported transgressions to gluten free diet and exhibited positivity for serum anti-tissue transglutaminase antibodies (tTG) and/or endomysial antibodies (EmA), compared with patients with occasional transgressions but negative for anti-tTG and/or -EmA, patients strictly adherent to the diet, and patients who suffered only from diabetes(ANOVA p=0.021). No difference was found between patients with diabetes alone and patients with both diseases strictly adherent to gluten free diet. Prevalence of osteopenia (z AD-SoS values <-2 SD) was higher in patients with T1DM and CD and poor compliance to the diet (45.5%) compared with patients with T1DM (8%) or patients with both diseases strictly compliant to diet (12.9%) (p=0.015). A negative correlation between Ad-SoS z score and HbA1c (r -0.236, p=0.036) was found when patients with T1DM and patients with T1DM and CD, who strictly adhere to the diet, were pooled. In conclusion the quality of bone as assessed by phalangeal ultrasound in patients with T1DM and CD, who strictly adhere to glutenfree diet, is similar to that found in T1DM patients. A higher prevalence of osteopenia is present in patients with both diseases who reported habitual transgressions to gluten free diet. The gluten free diet, as well as the optimization of glycemic control, plays an important role in preventing the osteopenic status caused by the clustering of these two chronic diseases.



Gluten Sensitivity in Multiple Sclerosis

Experimental Myth or Clinical Truth?

  1. Dana Ben-Ami Shor1,Ori Barzilai1, Maya Ram1, David Izhaky1, Bat Sheva Porat-Katz2, Joab Chapman3, Miri Blank1,
  2. Juan-Manuel Anaya4and Yehuda Shoenfeld1,5Article first published online: 1 SEP 2009

DOI: 10.1111/j.1749-6632.2009.04620.x





immunoglobulins;autoantibodies;autoimmunity;multiple sclerosis;gluten sensitivity


Patients with neurological disease of unknown etiology sometimes present with antigliadin and antitissue transglutaminase antibodies. The association between these antibodies and multiple sclerosis has been previously suggested. The purpose of this study was to determine the prevalence of these antibodies in multiple sclerosis patients. We determined the level of serum immunoglobulin A and immunoglobulin G antigliadin and antitissue transglutaminase antibodies in 98 patients with multiple sclerosis. We found a highly significant increase in titers of immunoglobulin G antibodies against gliadin and tissue transglutaminase in the multiple sclerosis patients. Seven patients had a positive IgG AGA, whereas only 2 controls presented positive titers (P= 0.03). Four patients had positive IgG anti-tTG while all the controls tested negative (P= 0.02). However, immunoglobulin A antibodies against gliadin and tissue transglutaminase were not statistically higher in the multiple sclerosis group in comparison to the control group. Our findings support the associations between antibodies against gliadin and tissue transglutaminase to multiple sclerosis. The specific role of these antibodies in the pathogenesis of multiple sclerosis remains uncertain and requires additional research. A gluten free diet should be considered in specific cases of patients who present with gluten antibodies.





Does cryptic gluten sensitivity play a part in neurological illness?


M Hadjivassiliou, MRCPcorrespondence, A Gibson, PhD, G.A.B Davies-Jones, MD, A.J Lobo, MD, T.J Stephenson, MD, A Milford-Ward, FRCPath




Background Antigliadin antibodies are a marker of untreated coeliac disease but can also be found in individuals with normal small-bowel mucosa. Because neurological dysfunction is a known complication of coeliac disease we have investigated the frequency of antigliadin antibodies, as a measure of cryptic gluten sensitivity, and coeliac disease in neurological patients.

Methods Using ELISA, we estimated serum IgG and IgA antigliadin antibodies in 147 neurological patients who were divided into two groups. There were 53 patients with neurological dysfunction of unknown cause despite full investigation (25 ataxia, 20 peripheral neuropathy, 5 mononeuritis multiplex, 4 myopathy, 3 motor neuropathy, 2 myelopathy). The remaining 94 patients were found to have a specific neurological diagnosis (16 stroke, 12 multiple sclerosis, 10 Parkinson’s disease, 56 other diagnoses) and formed the neurological control group. 50 healthy blood donors formed a third group.

Findings The proportions of individuals with positive titres for antigliadin antibodies in the three groups were 30/53, 5/94, and 6/50 respectively (57, 5, and 12%). The difference in proportion between group 1 and the combined control groups was 0·49 (95% Cl 0·35-0·63). Distal duodenal biopsies in 26 out of 30 antigliadin-positive patients from group 1 revealed histological evidence of coeliac disease in nine (35%), non-specific duodenitis in ten (38%), and no lesion in seven (26%) individuals.

Interpretation Our data suggest that gluten sensitivity is common in patients with neurological disease of unknown cause and may have aetiological significance.



Original Articles

Digestive Diseases and Sciences

August 1981, Volume 26, Issue 8, pp 737-740

First online:

Gluten-sensitive recurrent aphthous stomatitis

  • David Wray


Twenty selected patients with recurrent aphthous stomatitis in whom celiac disease had been specifically excluded were placed on a gluten-free diet. Five patients (25%) showed a favorable response to gluten withdrawal and a positive gluten challenge. Jejunal morphology was normal in all patients indicating gluten sensitivity without enteropathy. Gluten withdrawal provides a further method of treating some patients with recurrent aphthous stomatitis.



Case Report

Neurological Sciences

February 2008, Volume 29, Issue 1, pp 29-31

First online: 01 April 2008

A case of multiple sclerosis with atypical onset associated with autoimmune hepatitis and silent coeliac disease

Maria Teresa Ferrò , Diego Franciotta, Tommaso Riccardi, Elisabetta D’Adda, Elsa Mainardi,Alessandro Montanelli




Multiple sclerosis (MS) and coeliac disease (CD) are an uncommon association. Recently “MS-like illness and CNS white-matter abnormalities” have been demonstrated in patients with CD. We report the case of a 19-year-old female with MS, who presented an episode of headache at onset of disease and developed acute hepatitis (AH) 14 months later. After the diagnosis of AH, an occult CD, confirmed by jejunal biopsy, was disclosed. Constipation was the only gastrointestinal symptom. A serum sample collected before onset of MS was positive for CD. Anti-central nervous system antibodies were negative in both retrospective and current serum samples. Conclusions The concomitant presence of MS with atypical onset, AH and CD likely represents an unusual chance association in our patient but inflammatory immune-mediated damage of the central nervous system triggered by gluten could not be excluded.



Autoimmune hepatitis Coeliac disease Headache Multiple sclerosis White-matter abnormalities


Multiple autoimmune syndromes



Humbert P , Dupond JL

Service de Médecine Interne, Centre Hospitalier Universitaire Jean Minjoz, Besançon.


Annales de Medecine Interne [1988, 139(3):159-168]

Type: Journal Article, Review, Case Reports, English Abstract (lang: fre)


The possibility of three or more autoimmune diseases occurring in the same patient cannot be fortuitous and suggests a pathogenic relationship between each of them. In the light of 4 personal cases, the authors have recorded 87 reports of such associations in the literature, an analysis of which leads them to propose a classification of three types of multiple autoimmune syndrome. The grouping of these syndromes under a single heading should make the research and analysis of these morbid associations easier. Moreover, the classification adopted by the authors allows a more precise definition of patients with at least two autoimmune diseases and so helps to recognize the onset of a third autoimmune disease at a later date. Multiple autoimmune syndromes can be classified in 3 groups according to the prevalence of their associations one with another. Type I comprises myasthenia, thymoma, polymyositis and giant cell myocarditis, this association having a single pathogenic mechanism. Type II includes the Sjogren’s syndrome, rhumatoid arthritis, primary biliary cirrhosis, scleroderma and autoimmune thyroid disorders. Type III groups together 10 autoimmune diseases (autoimmune thyroid disease, myasthenia and/or thymoma, Sjogren’s syndrome, pernicious anaemia, idiopathic thrombocytopaenic purpura, Addison’s disease, insulin-dependent diabetes, vitiligo, autoimmune haemolytic anaemia, systemic lupus erythematosus) for which a genetic predisposition (phenotype HLA B8 and/or DR3 or DR5) seems to be an important factor.




Dermatological autoimmune diseases and the multiple autoimmune syndromes.



Humbert P , Dupond JL , Vuitton D , Agache P Dept. of Dermatology, Hôpital Saint-Jacques, Besançon, France. Acta Dermato-venereologica. Supplementum [1989, 148:1-8]

Type: Journal Article, Review

The association of autoimmune pathologies with cutaneous diseases has received little attention, except for their association by twos. The combination of at least three autoimmune diseases in a same patient has recently been defined as a Multiple Autoimmune Syndrome (MAS). The purpose of this article is to define the place of dermatological autoimmune conditions (vitiligo, alopecia areata, pemphigus, bullous pemphigoid, dermatitis herpetiformis) among the MAS and to stress the clinical aspects that may aid dermatologists in the care of their patients.