International Journal of Celiac Disease

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Authors: Aaron Lerner, Torsten Matthias

Prevalence of autoimmune thyroiditis is increased in patients with celiac disease and vice versa. Both diseases are frequent autoimmune diseases sharing multiple aspects lodging at the two ends of the gut-thyroid axis where the cross-talks’ pathways are still unrivalled. Many authors recommend screening patients with thyroid autoimmunity for celiac disease associated antibodies. However, routine screening of celiac patients for anti-thyroid antibodies is less clear. Despite the fact that the latter screening fulfills most of the criteria for screening a disease, the timing and cost-effectiveness remains undetermined. For now, in face of celiac disease, the increased prevalence of autoimmune thyroid diseases needs to be taken in account and the accurate diagnosis should not be delayed.

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Authors: Iulian Diaconescu, Giulia Alexandru, Rahela Carpa, Iulia Lupan, Corina Crisan, Lucia Sur, Genel Sur, Anamaria Girbovan

Introduction. Celiac disease has a prevalence of 1% of the global population and it is increasing every year. Viral infections such as hepatitis C and hepatitis B are the most common liver diseases and studies show that may be a link between them and celiac disease. Recent studies show attempts to find a link between viral infections and celiac disease. We focused our study on the association between viral infections and celiac disease. Material and Method. We studied 63 articles from the Pub Med Database that revealed a possible connection between viral infections and celiac disease. Results. Since it is more frequent, hepatitis C is associated with the development of celiac disease, but celiac disease is not the autoimmune manifestation of hepatitis C. Patients with celiac disease have a significantly decreased response to hepatitis B vaccine. Other viruses that are associated with celiac disease are: rotavirus, adenovirus, eterovirus and Epstein-Barr virus. Conclusions. The serological screening for celiac disease at hepatitis C patients, after starting treatment with interferon, is necessary. Also, it is justified the serological screening for celiac disease among adults infected with hepatitis B. Further studies are still needed to show the possible association of viral infections in the pathogenesis of celiac disease.

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Authors: Ketabimoghaddam Pardis, Dadvar Zohreh, Salehi Babak, Aletaha Najmeh, Allameh Seyed Farshad, Hassanpour Akbar, Talayi M.A

Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation. The upper 95th percentile in the for age for boys is 14 (an increase in testicular size being the first sign) and for girls is 12 (breast development being the first sign). Delayed puberty pathophysiologically is classified according to the circulating levels of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in to two groups of high serum LH/FSH and low or normal serum LH/FSH concentrations which are related to primary hypogonadism and hypothalamic dysfunction respectively. Patient Presentation. A 21 year old boy presented with severe respiratory distress syndrome due to pneumonia and generalized edema. Laboratory studies showed pancytopenia which made clinicians work up for hematologic disorders, leading to bone marrow aspiration and biopsy which was consistent with megaloblastic anemia resulting from vit B12 deficiency. Another manifestation of this patient was delayed puberty which had been ignored over these years. Evaluation of delayed puberty revealed a low serum LH/FSH concentration. Accompaniment of delayed puberty resulting from hypothalamic origin with edema and hypoalbuminemia made clinicians work up for a malabsorption syndrome. Therefore upper endoscopy and colonoscopy were done and duodenal biopsies were consistent with celiac sprue. The unusual symptom of this patient was vit B12 deficiency which is rare in celiac disease. Conclusion. Neglected celiac sprue can be accompanied by vit B12 deficiency probably because of involvement of more distal parts of small intestine over the time.

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Authors: Hugh J. Cornell, Teodor Stelmasiak

The importance of alternative or adjunct treatments to the gluten-free diet in celiac disease is now being recognized. This paper discusses the scientific principles behind the use of caricain for enzyme therapy. Objective: To review the structures of the toxic peptides in A-gliadin that relate to those found by other workers insofar as having key sequences of amino acids or motifs which relate to toxicity, especially in regard to difficulty of digestion or immunogenicity. Methods: Structures of synthetic A-gliadin peptides shown to be toxic in the fetal chick assay were examined before and after digestion with duodenal mucosa from patients in long remission. Synthetic peptides corresponding to the undigested residues were also assayed and the key amino acid sequences compared in order to determine if they could be related to direct toxicity and immunogenicity of the peptides. Results: The results showed that the smallest toxic peptides from celiac mucosal digestion were octa-peptides and that they were obtained in greater yield than similar products from normal digestion. One of those peptides corresponded to residues 12-19 of A-gliadin and contained the key motifs PSQQ and QQQP of De Ritis et al. , whilst the other corresponded to residues 72-79 and contained the key motif PYPQ (extending to PYPQPQ), observed by other workers, especially those who have been investigating immunological activity over the past two decades. Conclusions: The presence of key motifs in undigested residues from celiac mucosal digestion and the greater prevalence of these residues compared with residues from normal digestion justifies our work on enzyme therapy. These studies have also indicated that our use of caricain as an enzyme capable of digesting peptides with two different types of toxicity has a sound scientific basis.

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Authors: Lucia Maria Sur, Emanuela Floca, Genel Sur, Simona Rednic

Is celiac disease associated with arthritis? We will try to answer to this question by studying the last news in serological and genetic testing of celiac disease in juvenile arthritis and rheumatoid arthritis.

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Authors: Aaron Lerner, Torsten Matthias

Abnormalities in the gastric and duodenal eco-systems have been proposed as contributing to the pathophysiology of celiac disease (CD) and Helicobacter pylori (Hp) infection, respectively. Lymphocytic gastritis and lymphocytic duodenitis cohabit in Hp and celiac disease and also in Hp- or non-CD respective conditions. The present editorial discusses those entities, concentrating on the pathophysiological pathways, highlighting the Hp-CD relationship in the contest of the gut-stomach axis.

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Authors: Michael Megaly, Charl Khalil, Basim Tadros, Mariam Tawadros

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Authors: Aaron Lerner, Jeremias Patricia, Torsten Matthias

The gut ecosystem with myriads of microorganisms and the high concentration of immune system cells can be considered as a separate organ on its own. The balanced interaction between the host and microbial cells has been shaped during the long co-evolutionary process. In dysbiotic conditions, however, this balance is compromised and results in abnormal interaction between the host and microbiota. Celiac disease is such an example were dysbiotic and metabolic signature are shaping the disease progression in genetically susceptible individuals. Short chain fatty acids are bacterial originated metabolic messenger between the pathobionts and the intestinal mucosa. Their local luminal effects and systemic ones were just recently unraveled. Accumulating data attribute multiple beneficial effects to them. Changes in microbiota and their short-chain fatty acids production is clearly related to the pathogenesis of celiac disease and might open new therapeutic strategies to combat the disease.

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Authors: Gabriel Samasca

We continue to interview other personalities in the field of celiac disease. Professor Aaron Lerner, a member of our editorial board is introduced. His researches are well known by our readers.

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Authors: Gabriel Samasca, Pirvan Alexandru, Genel Sur, Abrudan Carmen, Iulia Lupan, Diana Deleanu

The celiac disease screening with IgA tissue transglutaminase antibodies depends on the cut-off reaction, therefore many patients with values less but close to the cut-off may be undiagnosed. Material and Method. We conducted the CD screening with IgA tissue transglutaminase antibodies in a group of 1616 children during 2014 at a cut-off of 25 U/ml and at a cut-off of 10 U/ml. We also wanted to compare our results with IgA tissue transglutaminase antibodies prevalence from other countries. Results. We found a IgA tissue transglutaminase antibodies prevalence rate of 3% for values higher 25 U/ml and a IgA tissue transglutaminase antibodies prevalence rate of 1.6% for values between 10-25 U/ml. A prevalence of 13.6% for IgA tissue transglutaminase antibodies was observed in Germany, Finland and Sweden. Conclusions. We observed a 4.6% IgA tissue transglutaminase antibodies prevalence at a cut-off of 10 U/ml. Prevalence of IgA tissue transglutaminase antibodies from Romania is lowered compared with other European countries.

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Authors: Valentina Sas, Camelia I. Bud, Ioana Fodor, Sorin C. Man

Celiac disease is an immune-mediated systemic disorder with a genetic predisposition. The availability of more specific serology tests showed that celiac disease is more common than previously suspected and that many patients do not demonstrate specific clinical or even histological sings. We present a case of celiac disease with the unset at 5 years, with recurrent episodes of diarrhea, weight loss and anemia. The serology tests showed a high level of IgA tissue transglutaminase antibodies, exceeding 10 times the upper limit but the intestinal biopsy showed normal size villi, intact surface epithelium and a lymphoplasmacytic infiltrate at chorionic level (Marsh 1). The diagnosis of celiac disease was confirmed by resolution of symptoms and normal tissue transglutaminase antibodies level, six month after starting the gluten free diet.

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Authors: Gabriel Samasca

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Authors: Marisa Spencer, Jason Baker, Abir Azeem, Joseph Dickens, Michael Rice, Laurel Fisher

Background: A proportion of patients with celiac disease are classified as having non-responsive celiac disease despite following a gluten free diet. This study seeks to clarify the appropriate use of video capsule endoscopy in non-responsive celiac disease patients. Methods: We retrospectively reviewed 32 patients with biopsy-proven celiac disease classified as having non-responsive celiac disease and referred for video capsule endoscopy at a single tertiary care center over 10 years. Results: 32 patients were categorized into those with ongoing gluten exposure at time of video capsule endoscopy (14), and those with strict gluten free diet compliance (18). Gluten free diet compliant patients were stratified by biopsy results: ongoing villous atrophy (3), no villous atrophy (6), or no biopsy data within 6 months (9). In patients with ongoing gluten exposure, video capsule endoscopy detected no concerning findings, and all patients ultimately improved with a gluten free diet. Among patients with recent negative biopsy, none had findings of celiac disease on their video capsule endoscopy and none developed complications related to celiac disease. However, in gluten free diet compliant patients with villous atrophy on biopsy, 2 of 3 were ultimately diagnosed with refractory celiac disease. Conclusions: Video capsule endoscopy may be useful in the evaluation of celiac disease in limited settings, namely after ongoing gluten exposure has been excluded and duodenal biopsy shows ongoing villous atrophy.

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Authors: Hugh J. Cornell, Agnieszka Czyzewska, Finlay A. Macrae, Grazyna Rydzewska, Anna Nasierowska-Gutmejer, Arkadiusz Bednarczuk, Teodor Stelmasiak

Background: The etiology of celiac disease (CD) is related to undigested fragments of gluten and gliadin which damage the small bowel. Mucosal enzyme deficiency is an important factor in CD pathology. A clinical trial has shown that the effects of a gluten challenge to patients with CD could be ameliorated by the use of an enzyme supplement. Objective: Enzyme therapy using enterically coated tablets containing caricain (Gluteguard) was investigated as a means of protecting patients with CD against wheat gluten. Methods: A randomized placebo-controlled trial was carried out on 20 CD patients in clinical remission. The patients were divided into a group of 14 given Gluteguard and a group of 6 given a placebo daily. Both groups were given a challenge of 1g of gluten daily. Symptoms were graded and recorded over a period of 42 days. Duodenal tissue was taken at the beginning and end of this period, together with blood for assay of tissue transglutaminase (tTG-IgA) antibodies. Results: The results showed that oral enzyme therapy based on caricain, was effective in ameliorating the symptoms of CD giving a statistically significant difference between treatment and placebo (P<0.01) after 14 days challenge. General well-being was also improved from 6.1 to 8.4 (P< 0.01) by the enzyme therapy. Four of the six placebo group patients (67%) and one of the 14 treatment patients (7%) to withdraw from gluten challenge after 14 days due to development of serious symptoms. The difference between the groups was significant (p < 0.001). For the per protocol patients on Gluteguard therapy, there were no significant changes in markers of histological damage or biopsy results after 42 days of gluten challenge. Conclusions: This study demonstrated that oral anti-gluten enzyme therapy using Gluteguard was able to significantly protect celiac patients from adverse symptoms being induced by gluten challenge. Furthermore, mucosal damage was not exacerbated in patients taking Gluteguard along with their daily gluten challenge, suggesting that the enzyme tablets may also help with the recovery of epithelium in the longer term. Availability of a preventative enzyme treatment like Gluteguard will likely add to the quality of life and well-being of coeliac patients, especially those who have difficulty in strictly adhering to a gluten-free diet.

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Authors: Andreea L. Rachisan, Alexandru Pirvan, Nicolae Miu, Dan Gheban, Adrian Hrusca, Gabriel Samasca, Iulia Lupan

The “four out of five rule” has not been officially endorsed by official guidelines. However, HLA-associated genes that predispose to CD are found in as much as 30–40% of healthy people. Thus, their presence seems too indecisive for the occurrence of CD.

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Authors: Aaron Lerner, Torsten Matthias

The gold standard for diagnosis of celiac disease is positive serology confirmed by histological evidence of small intestinal biopsy damage as determined by the modified Marsh classification. Intraepithelial lymphocyte count has a pivotal importance in this grading criteria and the normal cut-off density has paramount importance in distinguishing between celiac disease and normal or false+ conditions. However its determination is problematic, complicated and far from being standardized. The localization along the villi or along the small bowel, the section thickness, the mode of detection and analysis, geoepidemiological influences, age dependency, associated infections or diseases and the strictness of the inclusions/exclusion criteria of the normal control group, all affect IEL density and normal cut-off levels. It is hoped that after standardization, the cut-off levels of IELs will better reflect the in-vivo reality to distinguish celiac disease from normal and associated conditions that affect intestinal IEL count.

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Authors: Hugh James Freeman

Celiac disease is an immune-mediated small intestinal mucosal disorder with characteristic, but non-specific histopathological changes. A number of heterogeneous disorders may produce similar changes in small bowel biopsies, but these fail to respond to a gluten-free diet. Recently, it has become increasingly appreciated that different medications may cause this sprue-like intestinal disease, including a specific angiotensin II receptor antagonist, olmesartan, an agent often used for treatment of hypertension. This enteropathy appears to occur as an apparently rare adverse event, often presenting with severe diarrhea, malabsorption and weight loss following chronic long-term use of the drug. Serological studies, particularly for tissue transglutaminase IgA antibodies, are negative and biopsies may show moderate to severe changes in mucosal architecture similar to celiac disease. Sub-epithelial collagen deposits may also occur. Clinical and biopsy changes fail to respond to a strict gluten-free diet, but cessation of olmesartan use appears to result in resolution.

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Authors: Ludmila Tankova, Vanya Gerova, Plamen Getsov, Nikolay Penkov, Gergana Taneva, Ivan Terziev, Radislav Nakov

Concomitant occurrence of celiac disease (CeD) and Crohn’s disease (CD) is rare and has been reported in several case reports and series. We report a case of a 63-year-old man with proximal CD, CeD and selective immunoglobulin (Ig) A deficiency (SIgAD). The patient was admitted in our Clinic for evaluation of epigastric pain, nausea, vomiting and weight loss (up to 7 kg) appeared in the last 3 months. The imaging findings from abdominal ultrasound and CT enterography raised suspicion of a lymphoproliferative disease of the jejunum. To exclude the development of lymphoma based on long standing untreated atypical CeD, upper endoscopy with biopsies and serological tests were conducted, showing and subtotal villous atrophy and elevated levels of IgG tissue transglutaminase tTG. Histopathology documented CD (A3,L4,B2 according to Montreal’s classification).

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Authors: Aaron Lerner, Torsten Matthias

Metabolic bone disease is a frequent extra-intestinal co-morbidity in newly diagnosed, mostly adult patients who have 70% low bone mineral density. Musculoskeletal signs and symptoms, osteopenia, osteoporosis and fractures are the most frequent manifestations. The etiology is multifactorial, however, micronutrient malabsorption, mainly of calcium and vitamin D, secondary hyperparathyroidism and inflammation are the main driving forces. The diagnosis is based on signs and symptoms, biochemical and endocrinologic laboratory evaluation and imaging by dual x-ray absorptiometry. Treatment of low bone mineral density in CD comprises: a gluten free diet, coverage of nutritional deficiencies (including calcium and vitamin D), changes in life style and if necessary, pharmacologic and hormonal replacement therapy. The cost effectiveness of those therapy methods were barely assessed. Understanding the pathophysiology of bone loss in celiac disease might bring new therapeutical strategies for the patient’s benefit.

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Authors: Florina Maria Gabor-Harosa, Gabriel Samasca, Ovidiu Petru Stan, Floarea Mocean

A new entity was included in the gluten diseases: the non-celiac gluten sensitivity. But the non-celiac gluten sensitivity is not yet clearly defined and its diagnosis is difficult. These lead us to implement a national register for the patients with non-celiac gluten sensitivity.

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Authors: Eranga Himalee Siriweera, Zhengyan Qi, Jim. L. C. Yong

The gold standard for diagnosis of Celiac disease (CD) is histological evidence of a small intestinal biopsy together with positive serology. Modified Marsh classification utilizes the histological parameter of intraepithelial lymphocyte (IEL) count in the diagnosis of CD. The reported upper limit of normal IEL in the duodenum varies from 20-40 per 100 epithelial cells (EC). The objectives of the study are to determine the normal upper limit of IEL in the duodenum and assess the diagnostic accuracy of existing criteria of IEL counts to diagnose CD. A retrospective analysis of histopathological records of duodenal biopsies reported as normal (control group, n=38) and consistent with CD (n=37) formed the basis of the study. IEL were counted in an uninterrupted length of surface epithelium and villous tips from formalin fixed, paraffin embedded, Haematoxylin and Eosin stained biopsies under the light microscope (X400 magnification). In the control group the mean IEL/100EC was 3.81(upper limit of normal = 7.78) and the mean IEL/villous tip was 0.96 (upper limit of normal = 3.5). In CD the mean IEL/100EC and mean IEL/villous tip were 20.93 and 6.83 respectively. The upper limit of normal IEL/100EC, mean IEL/100EC in CD and the villous tip IEL count in both the control and CD groups were considerably lower than those reported in other studies. The ethnicity, country of origin and environmental factors may be partly responsible for this observation. If high cut off values of IEL/100EC is taken to diagnose CD many cases may be under diagnosed, particularly when the upper limit of the normal IEL count is lower for that population and region, highlighting the importance of a multidisciplinary approach in the diagnosis of CD.

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Authors: Dorottya Kocsis, László Herszényi, Miklós Tóth, Zsolt Tulassay, Márk Juhász

Introduction. The association of celiac disease and facioscapulohumeral muscular dystrophy was not reported earlier in the literature. Case presentation. A 35-year-old woman diagnosed clinically with facioscapulohumeral muscular dystrophy 23 years ago. In the family history patients’ mother was diagnosed with facioscapulohumeral muscular dystrophy, too. Physical examination revealed bilateral facial weakness, she had narrow smile and murmuring speech. She had low-degree atrophy of shoulder girdle muscles with left-dominated scapular winging. facioscapulohumeral muscular dystrophy DNA testing showed allele 1 deletion. From 2001 on, patient presented epigastrial pain, diarrhoea, weight loss. She had permanent fatigue and she was unable to do regular physical exercises, which led to the progression of muscular dystrophy. Since serological examination detected elevated tissue transglutaminase and deaminated gliadin peptide antibodies levels, and duodenal biopsy revealed subtotal villous atrophy. Celiac disease was diagnosed. She started strict gluten free diet. After 3 months of gluten free diet, patient reported the elimination of gastrointestinal symptoms, better general condition, weight gain and increased muscle strength. Conclusion. Appropriate nutrition is essential for facioscapulohumeral muscular dystrophy patients, therefore detection and treatment of any disorders leading to malabsorption, most commonly celiac disease, are of utmost importance.

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Authors: Aaron Lerner, Patricia Jeremias, Torsten Matthias

Epidemiological data provide evidence of a steady rise in autoimmune disease throughout Westernized societies over the last decades. Multiple publications exist, describing past or actual incidences/prevalence of individual autoimmune diseases, however, long term studies on selected populations are scarce. Aims: to calculate the % increases per year of autoimmune diseases frequencies worldwide, analyze the differential increases per country and disease, and identify geoepidemiological trends. Methods: A systematic review was performed to identify incidence and prevalence of autoimmune diseases. 30 Studies from the last 30 years were identified using Medline, Google, and Cochrane Library databases. Only long-term regional or national follow-ups are reported. Results: The means ± s.d. of the net % increased /year incidence and prevalence of autoimmune diseases worldwide were 19.1±43.1 and 12.5±7.9, respectively. Rheumatic, endocrinological, gastrointestinal and neurological autoimmune diseases revealed the following annual % increases per year: 7.1, 6.3, 6.2, and 3.7, respectively. In all of these, differences between old vs new frequencies were highly significant (p< 0.0001). Comparing various autoimmune diseases, celiac disease increased the most and the highest increase in incidence, comparing old to new surveys is allocated to myasthenia gravis. Despite considerable variations between the countries, celiac, type 1 diabetes and myasthenia gravis frequencies increased the most in Canada, Israel and Denmark, respectively. Frequencies of the autoimmune diseases increased significantly in the West and North when compared to East and South, respectively. Conclusions: Despite multiple reports on autoimmune diseases frequencies, long-term longitudinal follow-ups are scarce. Incidences and prevalences have increased significantly over the last 30 years. Rheumatic, endocrinological and gastrointestinal autoimmune diseases in Israel, Netherlands, USA and Sweden increased the most. These observations point to a stronger influence of environmental factors as opposed to genetic factors on autoimmune disease development.

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Authors: Andrej Beseda, Marián Bencat, Lubica Korinkova, Janka Papanová, Julius Rajcani

The most frequent cause of malabsorption syndrome (MAS) in developed countries is the celiac disease (CD). There are two possible approaches for exact diagnostic of this disorder: in case of full blown clinical symptoms the golden standard is duodenal biopsy. When it shows classical mucosa lesions (Marsh type 3 mucosa atrophy of various grades), the diagnosis of CD is confirmed. However, if intraepithelial lymphocyte infiltration (IEL) and/or hyperplastic crypts can be seen in the absence of mucosa atrophy (Marsh type 1 and/or 2 lesions) only, it is reasonable to examine the serologic markers. The most frequent enzyme linked immunosorbent assay (ELISA) tests are: detection of tissue transglutaminase 2 antibody (anti-tTGase 2, especially of IgA class) and the deamidated gliadin peptide antibody (anti-DGP) assay. A simpler serological test, useful for screening, is the detection of anti-endomysium antibody (AEmA) by indirect fluorescent antibody (IFA) in monkey intestine or esophagus sections. This is reasonable to combine with the microdot test for anti-gliadin antibody (AGA), especially by using the endomysium/gliadin mosaic kit (Euroimmun). Taken together, at least three serological markers (anti-tTGase 2, anti-DGP and AGA) are highly specific for CD; their detection first (i.e. prior to duodenal biopsy) is recommended in children as well as in adults showing atypical, silent and or latent forms of CD. In both of them, serology represents a reliable non-invasive approach, which allows precise diagnosis with a probability of nearly 90 %. Another advantage of the non-invasive serological technic is that it can be easily repeated when following the outcome of gluten-free diet (GFD). Nevertheless, duodenal biopsy should be performed in any case, if the serology does not correlate with clinical symptoms. In such patients as well as in those revealing positive serology but negative and/or non-specific histology, immunogenetic typing should be performed in order to assess the expression of DQ2 [DQA*0501-DQB*0201] or DQ8 [DQA*0301-DQB1*0302] haplotypes of the human leukocyte antigen (HLA) class II region critical for the development of CD.