Uveitis in celiac disease with an excellent response to gluten-free diet: third case described

To describe the case of a patient with celiac disease who achieved a complete response to a gluten-free diet. A 28-year-old woman presented with diarrhea, oral ulcers, and refractory uveitis of 2.5-years duration. She was treated with prednisone, mydriatic drops, and infliximab with no response. She was referred to our hospital at which point her previous diagnosis of uveitis was confirmed; she was also diagnosed with right-sided sacro-iliitis. The patient did not have arthritis or any skin conditions. Three tests for fecal parasites and a fecal leukocyte were negative. Endoscopy revealed atrophic appearance of the duodenal mucosa. Biopsy showed atrophy of the duodenal villi with intra-epithelial lymphocytes, hyperplasia of the crypts, and chronic inflammatory infiltrate. The search for antiendomysial antibody was > 1/1,280. The patient was started on a gluten-free diet and after 3 months demonstrated significant improvement of gastrointestinal symptoms and uveitis, as well as a reduction of antiendomysial antibodies (1/80). After 6 months, there was complete remission of gastrointestinal symptoms and total control of uveitis. The antiendomysial antibody was negative at that time. Clinical uveitis as a manifestation of celiac disease has been described in only two cases in the literature. This case study is the third to demonstrate that uveitis is a clinical symptom that can be addressed in patients with celiac disease.

Prevalence of celiac disease in Brazilian children of short stature

The aim of the present study was to determine the prevalence of celiac disease in children of short stature and to assess whether some of the routine laboratory examinations performed to determine the cause of short stature could suggest the presence of celiac disease. A total of 106 children of short stature and no gastrointestinal symptoms were studied. An extensive endocrine work-up had been negative for all of them and an additional investigation was performed by measuring the concentration of antiendomysial antibody. Patients who were positive for antiendomysial antibody ( > or = 1:10) or who exhibited IgA deficiency (less than 5 mg/dl) were referred for an endoscopic intestinal biopsy. We detected a pathological titer of antiendomysial IgA in six of these patients. Five of them showed histological abnormalities compatible with celiac disease and one had normal histology and was considered to have potential celiac disease. The prevalence of celiac disease in the population studied was 4.7% (with another 0.9% of the subjects being considered to have potential celiac disease). The children with celiac disease did not differ in any of the parameters tested when compared to those without celiac disease, though they showed an improvement in growth velocity after treatment with a gluten-free diet. We conclude that it is important to test all children with short stature for celiac disease by measuring antiendomysial IgA.

Une nouvelle stratégie de traitement de la maladie cœliaque basée sur les polymères séquestrants

La maladie cœliaque ou sprue cœliaque est une intolérance au gluten. Il s’agit d’une maladie inflammatoire de l’intestin liée à l’ingestion de gluten chez des personnes génétiquement susceptibles. Ce désordre présente une forte prévalence puisqu’il touche 1 % de la population mondiale. En l’état actuel des choses, il n’existe aucun outil pharmacologique pour traiter ou pallier à cette maladie. Cependant, grâce aux avancées dans la compréhension de sa pathogenèse, de nouvelles cibles thérapeutiques ont été identifiées. À l’heure actuelle, le seul traitement efficace consiste à suspendre la consommation de l’agent pathogène, à savoir le gluten. Le gluten est un ensemble de protéines de stockage des céréales contenu dans le blé, l’orge et le seigle. Le gluten du blé se subdivise en gluténines et gliadines. Ce sont ces dernières qui semblent les plus impliquées dans la maladie cœliaque. Les gliadines et ses protéines apparentées (i.e. sécalines et hordéines, respectivement dans le seigle et l’orge) sont riches en prolines et en glutamines, les rendant résistantes à la dégradation par les enzymes digestives et celles de la bordure en brosse. Les peptides résultant de cette digestion incomplète peuvent induire des réponses immunitaires acquises et innées. L’objectif principal de cette thèse était de tester un nouveau traitement d’appoint de la maladie cœliaque utile lors de voyages ou d’évènements ponctuels. Dans les années 80, une observation italienne montra l’inhibition de certains effets induits par des gliadines digérées sur des cultures cellulaires grâce à la co-incubation en présence de mannane: un polyoside naturel composé de mannoses. Malheureusement, ce traitement n’était pas applicable in vivo à cause de la dégradation par les enzymes du tractus gastro-intestinales du polymère, de par sa nature osidique. Les polymères de synthèse, grâce à la diversité et au contrôle de leurs propriétés physico-chimiques, se révèlent être une alternative attrayante à ce polymère naturel. L’objectif de cette recherche était d’obtenir un polymère liant la gliadine, capable d’interférer dans la genèse de la maladie au niveau du tube digestif, afin d’abolir les effets délétères induits par la protéine. Tout d’abord, des copolymères de type poly (hydroxyéthylméthacrylate)-co-(styrène sulfonate) (P(HEMA-co-SS)) ont été synthétisés par polymérisation radicalaire contrôlée par transfert d’atome (ATRP). Une petite bibliothèque de polymères a été préparée en faisant varier la masse molaire, ainsi que les proportions de chacun des monomères. Ces polymères ont ensuite été testés quant à leur capacité de complexer la gliadine aux pH stomacal et intestinal et les meilleurs candidats ont été retenus pour des essais cellulaires. Les travaux ont permis de montrer que le copolymère P(HEMA-co-SS) (45:55 mol%, 40 kDa) permettait une séquestration sélective de la gliadine et qu’il abolissait les effets induits par la gliadine sur différents types cellulaires. De plus, ce composé interférait avec la digestion de la gliadine, suggérant une diminution de peptides immunogènes impliqués dans la maladie. Ce candidat a été testé in vivo, sur un modèle murin sensible au gluten, quant à son efficacité vis-à-vis de la gliadine pure et d’un mélange contenant du gluten avec d’autres composants alimentaires. Le P(HEMA-co-SS) a permis de diminuer les effets sur les paramètres de perméabilité et d’inflammation, ainsi que de moduler la réponse immunitaire engendrée par l’administration de gliadine et celle du gluten. Des études de toxicité et de biodistribution en administration aigüe et chronique ont été réalisées afin de démontrer que ce dernier était bien toléré et peu absorbé suite à son administration par la voie orale. Enfin des études sur des échantillons de tissus de patients souffrants de maladie cœliaque ont montré un bénéfice therapeutique du polymère. L’ensemble des travaux présentés dans cette thèse a permis de mettre en évidence le potentiel thérapeutique du P(HEMA-co-SS) pour prévenir les désordres reliés à l’ingestion de gluten, indiquant que ce type de polymère pourrait être exploité dans un avenir proche.

Recent advances in the development of tissue transglutaminase (TG2) inhibitors

Tissue transglutaminase (TG2) is a Ca2+-dependent enzyme and probably the most ubiquitously expressed member of the mammalian transglutaminase family. TG2 plays a number of important roles in a variety of biological processes. Via its transamidating function, it is responsible for the cross-linking of proteins by forming isopeptide bonds between glutamine and lysine residues. Intracellularly, Ca2+ activation of the enzyme is normally tightly regulated by the binding of GTP. However, upregulated levels of TG2 are associated with many disease states like celiac sprue, certain types of cancer, fibrosis, cystic fibrosis, multiple sclerosis, Alzheimer's, Huntington's and Parkinson's disease. Selective inhibitors for TG2 both cell penetrating and non-cell penetrating would therefore serve as novel therapeutic tools for the treatment of these disease states. Moreover, they would provide useful tools to fully elucidate the cellular mechanisms TG2 is involved in and help comprehend how the enzyme is regulated at the cellular level. The current paper is intended to give an update on the recently discovered classes of TG2 inhibitors along with their structure-activity relationships. The biological properties of these derivatives, in terms of both activity and selectivity, will also be reported in order to translate their potential for future therapeutic developments. © 2011 Springer-Verlag.

Serological testing for celiac disease in women with endometriosis. A pilot study

Purpose of Investigation: Celiac disease (CD) involves immunologically mediated intestinal damage with consequent micronutrient malabsorption and varied clinical manifestations, and there is a controversial association with infertility. The objective of the present study was to determine the presence of CD in a population of infertile women with endometriosis. Methods: A total of 120 women with a diagnosis of endometriosis confirmed by laparoscopy (study group) and 1,500 healthy female donors aged 18 to 45 years were tested for CD by the determination of IgA-transglutaminase antibody against human tissue transglutaminase (t-TGA) and anti-endomysium (anti-EMA) antibodies. Results: Nine of the 120 women in the study group were anti-tTGA positive and five of them were also anti-EMA positive. Four of these five patients were submitted to intestinal biopsy which revealed CD in three cases (2.5% prevalence). The overall CD prevalence among the population control group was 1:136 women (0.66%). Conclusion: This is the first study reporting the prevalence of CD among women with endometriosis, showing that CD is common in this population group (2.5%) and may be clinically relevant.

Prevalence of celiac disease among blood donors in Sao Paulo - the most populated city in Brazil

OBJECTIVE: Celiac disease is a permanent enteropathy caused by the ingestion of gluten, which leads to an immune-mediated inflammation of the small intestine mucosa. The prevalence of celiac disease varies among different nations and ethnic backgrounds, and its diversity is determined by genetic and environmental factors. Sao Paulo city is one of the largest cities in the world, with a vast population and an important history of internal migratory flow from other Brazilian regions, as well as immigration from other, primarily European, countries, resulting in significant miscegenation. The aim of the present study was to estimate the prevalence of adults with undiagnosed celiac disease among blood donors of Sao Paulo by collecting information on the ancestry of the population studied. METHODS: The prevalence of celiac disease was assessed by screening for positive IgA transglutaminase and IgA endomysium antibodies in 4,000 donors (volunteers) in the Fundacao Pro-Sangue Blood Center of Sao Paulo, Sao Paulo, Brazil. The antibody-positive subjects were asked to undergo a small bowel biopsy. RESULTS: Of the 4,000 subjects, twenty-four had positive tests, although both antibody tests were not always concordant. For example, ten subjects were positive for IgA tissue transglutaminase only. In twenty-one positive patients, duodenal biopsies were performed, and the diagnosis of celiac disease was confirmed in fourteen patients (Marsh criteria modified by Oberhuber). In this group, 67% claimed to have European ancestry, mainly from Italy, Portugal and Spain. CONCLUSION: The prevalence of celiac disease is at least 1: 286 among supposedly healthy blood bank volunteers in Sao Paulo, Brazil.

Metabolic osteopathy in celiac disease: importance of a gluten-free diet

Reduced bone mineral density (BMD) is frequently found in individuals with untreated celiac disease (CD), possibly due to calcium and vitamin D malabsorption, release of pro-inflammatory cytokines, and misbalanced bone remodeling. A gluten-free diet (GFD) promotes a rapid increase in BMD that leads to complete recovery of bone mineralization in children. Children may attain normal peak bone mass if the diagnosis is made and treatment is given before puberty, thereby preventing osteoporosis in later life. A GFD improves, but rarely normalizes, BMD in patients diagnosed with CD in adulthood. In some cases, nutritional supplementation may be necessary. More information on therapeutic alternatives is needed

Behcet`s disease associated with celiac disease: a very rare association

There are common findings between Beh double dagger et`s disease (BD) and celiac disease (CD); however, association in the same patient is a rarity. We relate the third case in the literature of this overlap in a 40-year-old woman with history of obstipation since her childhood. She also presented asymmetric polyarthralgia, loss of weight, anemia, oral recurrent aphthas (> 3/year) and genital ulcerations, inflammatory lower back pain, bowel bleeding and abdominal colic. Afterwards, she presented episodes of erythema nodosum, superficial thrombophlebitis, pseudofolliculitis and aseptic meningitis, thus fulfilling criteria for BD. Due to persistence of the digestive complaints, a gastrointestinal endoscopy was performed. The biopsy showed chronic duodenitis with intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy. Endomysial antibody was positive. She fulfilled the diagnosis criteria for CD; a gluten-free diet was applied with clinical improvement. Ascertaining whether pathogenic mechanisms are common in these two conditions requires further investigation.

Celiac disease detection using a transglutaminase electrochemical immunosensor fabricated on nanohybrid screen-printed carbon electrodes

Celiac disease is a gluten-induced autoimmune enteropathy characterized by the presence of tissue tranglutaminase (tTG) autoantibodies. A disposable electrochemical immunosensor (EI) for the detection of IgA and IgG type anti-tTG autoantibodies in real patient’s samples is presented. Screen-printed carbon electrodes (SPCE) nanostructurized with carbon nanotubes and gold nanoparticles were used as the transducer surface. This transducer exhibits the excellent characteristics of carbon–metal nanoparticle hybrid conjugation and led to the amplification of the immunological interaction. The immunosensing strategy consisted of the immobilization of tTG on the nanostructured electrode surface followed by the electrochemical detection of the autoantibodies present in the samples using an alkaline phosphatase (AP) labelled anti-human IgA or IgG antibody. The analytical signal was based on the anodic redissolution of enzymatically generated silver by cyclic voltammetry. The results obtained were corroborated with a commercial ELISA kit indicating that the electrochemical immunosensor is a trustful analytical screening tool.

Voltammetric immunosensor for the diagnosis of celiac disease based on the quantification of anti-gliadin antibodies

Antibodies against gliadin are used to detect celiac disease (CD) in patients. An electrochemical immunosensor for the voltammetric detection of human anti-gliadin antibodies (AGA) IgA and AGA IgG in real serum samples is proposed. The transducer surface consists of screen-printed carbon electrodes modified with a carbon nanotube/gold nanoparticle hybrid system, which provides a very useful surface for the amplification of the immunological interactions. The immunosensing strategy is based on the immobilization of gliadin, the antigen for the autoantibodies of interest, onto the nanostructured surface. The antigen–antibody interaction is recorded using alkaline phosphatase labeled anti-human antibodies and a mixture of 3-indoxyl phosphate with silver ions (3-IP/Ag+) was used as the substrate. The analytical signal is based on the anodic redissolution of the enzymatically generated silver by cyclic voltammetry. The electrochemical behavior of this immunosensor was carefully evaluated assessing aspects as sensitivity, non-specific binding and matrix effects, and repeatability and reproducibility. The results were supported with a commercial ELISA test.

Celiac disease diagnosis and gluten-free food analytical control

Celiac disease (CD) is an autoimmune enteropathy, characterized by an inappropriate T-cell-mediated immune response to the ingestion of certain dietary cereal proteins in genetically susceptible individuals. This disorder presents environmental, genetic, and immunological components. CD presents a prevalence of up to 1% in populations of European ancestry, yet a high percentage of cases remain underdiagnosed. The diagnosis and treatment should be made early since untreated disease causes growth retardation and atypical symptoms, like infertility or neurological disorders. The diagnostic criteria for CD, which requires endoscopy with small bowel biopsy, have been changing over the last few decades, especially due to the advent of serological tests with higher sensitivity and specificity. The use of serological markers can be very useful to rule out clinical suspicious cases and also to help monitor the patients, after adherence to a gluten-free diet. Since the current treatment consists of a life-long glutenfree diet, which leads to significant clinical and histological improvement, the standardization of an assay to assess in an unequivocal way gluten in gluten-free foodstuff is of major importance.

An electrochemical deamidated gliadin antibody immunosensor for celiac disease clinical diagnosis

The first electrochemical immunosensor (EI) for the detection of antibodies against deamidated gliadin peptides (DGP) is described here. A disposable nanohybrid screen-printed carbon electrode modified with DGP was employed as the transducer's sensing surface. Real serumsampleswere successfully assayed and the results were corroborated with an ELISA kit. The presented EI is a promising analytical tool for celiac disease diagnosis.

Multiplexed electrochemical immunosensor for detection of celiac disease serological markers

Celiac disease (CD) is a gluten-induced autoimmune enteropathy characterized by the presence of antibodies against gliadin (AGA) and anti-tissue transglutaminase (anti-tTG) antibodies. A disposable electrochemical dual immunosensor for the simultaneous detection of IgA and IgG type AGA and antitTG antibodies in real patient’s samples is presented. The proposed immunosensor is based on a dual screen-printed carbon electrode, with two working electrodes, nanostructured with a carbon–metal hybrid system that worked as the transducer surface. The immunosensing strategy consisted of the immobilization of gliadin and tTG (i.e. CD specific antigens) on the nanostructured electrode surface. The electrochemical detection of the human antibodies present in the assayed serum samples was carried out through the antigen–antibody interaction and recorded using alkaline phosphatase labelled anti-human antibodies and a mixture of 3-indoxyl phosphate with silver ions was used as the substrate. The analytical signal was based on the anodic redissolution of enzymatically generated silver by cyclic voltammetry. The results obtained were corroborated with commercial ELISA kits indicating that the developed sensor can be a good alternative to the traditional methods allowing a decentralization of the analyses towards a point-of-care strategy.