Are the dietary habits of treated individuals with celiac disease adherent to a Mediterranean diet?

BACKGROUND AND AIMS: The only treatment for celiac disease (CD) is strict, lifelong adherence to a gluten-free (GF) diet. To date, there are contrasting data concerning the nutritional adequacy of GF products and diet. There have been no studies that have assessed the adherence of individuals with CD to a Mediterranean diet (MD), a protective dietary regimen against major non-communicable diseases (NCDs). Therefore, we examined the adherence to an MD of a group of Italian individuals with CD and compared it with that of a healthy control group. METHODS AND RESULTS: In a cross-sectional study, a sample of individuals with CD and a group of healthy subjects were included. The dietary habits of all participants were recorded using a validated food frequency questionnaire, and the adherence to an MD was determined using the Italian Mediterranean Index. Typical Mediterranean food consumption was not significantly different between individuals with CD and the healthy participants, except for fruits (P = 0.017). However, individuals with CD consumed significantly higher amounts of potatoes (P = 0.003) and red and processed meat (P = 0.005) than healthy participants. The resulting mean Italian Mediterranean Index was significantly higher in healthy participants than in individuals with CD (P < 0.001). CONCLUSION: The results raise questions concerning the food choices of individuals with CD, suggesting the need of encouraging them to make better food choices more in line with an MD, which would improve their nutritional status and better protect them from NCDs at long term. PROTOCOL REGISTRATION: ClinicalTrials.gov (ID NCT01975155) on November 4 2013.

Megaduodenum: an unusual presentation of amyloidosis?

Amyloidosis, a potentially fatal disease, is characterized by an abnormal deposition of autologous proteins. Heart, liver, kidneys, lung, thyroid, skin and the gastrointestinal tract can be involved; in this last case mucosal alterations or disturbances of the motility leading to pseudo-obstruction, bleeding, diarrhea and malabsorption can be present. However, the data concerning the possible gastrointestinal presentations of amyloidosis are scanty and heterogeneous. We report the case of a patient presenting severe gastrointestinal symptoms caused by a megaduodenum. The patient was thoroughly investigated and lesions appeared limited to the upper gastrointestinal tract in the absence of a systemic disorder. However, at follow up the patient developed cardiac dilatation and bioptic samples revealed the presence of amyloidosis.

Evaluation of GH-IGF-I axis in adult patients with coeliac disease.

The aim of this study was to evaluate GH/IGF-I axis and other pituitary functions in adult patients with coeliac disease. For this purpose, twenty-eight adult coeliac patients [20M, 8F:19-74 years; body mass index (BMI): 18.5-28 kg/m (2)] were recruited. Basal thyroid, adrenal and gonadal function, serum IGF-I and PRL, and routine parameters were evaluated. Dynamic GH secretion was carried out by GHRH plus arginine test. In 20 patients, antipituitary antibodies (APA) were also evaluated. Seven out of 28 patients, independently from disease onset and the gluten-free diet (GFD), showed an impaired GH secretion (25%). All were males, 2 with severe growth hormone deficiency (GHD) and 5 with partial GHD. In patients with GHD, as compared to coeliac patients with normal GH secretion, HOMA (2.1+/-1.2 vs. 0.9+/-0.4) and QUICKI (0.35+/-0.03 vs. 0.39+/-0.02) levels were significantly higher and lower, respectively, while IGF-I levels were slightly lower (17.7+/-3.7 vs. 24.7+/-6.3, p=NS). APA were negative in all 20 patients studied. In conclusion, a significant number of adult coeliac patients show an impaired GH secretion, this alteration being predominant in males and independent from disease onset and diet regimen. Given the absence of APAs, the cause of this pituitary dysfunction remains unclear even if a previous autoimmune involvement in some cases cannot be excluded.

Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver.

Transglutaminases are a family of eight currently known calcium-dependent enzymes that catalyze the cross-linking or deamidation of proteins. They are involved in important biological processes such as wound healing, tissue repair, fibrogenesis, apoptosis, inflammation and cell-cycle control. Therefore, they play important roles in the pathomechanisms of autoimmune, inflammatory and degenerative diseases, many of which affect the gastrointestinal system. Transglutaminase 2 is prominent, since it is central to the pathogenesis of celiac disease, and modulates inflammation and fibrosis in inflammatory bowel and chronic liver diseases. This review highlights our present understanding of transglutaminase function in gastrointestinal and liver diseases and therapeutic strategies that target transglutaminase activities.

Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.

OBJECTIVE: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). RESULTS: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. CONCLUSIONS: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease.

BACKGROUND AND AIMS: The first genome wide association study on coeliac disease (CD) and its follow-up have identified eight new loci that contribute significantly towards CD risk. Seven of these loci contain genes controlling adaptive immune responses, including IL2/IL21 (4q27), RGS1 (1q31), IL18RAP (2q11-2q12), CCR3 (3p21), IL12A (3q25-3q26), TAGAP (6q25) and SH2B3 (12q24). METHODS: We selected the nine most associated single nucleotide polymorphisms to tag the eight new loci in an Italian cohort comprising 538 CD patients and 593 healthy controls. RESULTS: Common variation in IL2/IL21, RGS1, IL12A/SCHIP and SH2B3 was associated with susceptibility to CD in our Italian cohort. The LPP and TAGAP regions also showed moderate association, whereas there was no association with CCR3 and IL18RAP. CONCLUSION: This is the first replication study of six of the eight new CD loci; it is also the first CD association study in a southern European cohort. Our results may imply there is a genuine population difference across Europe regarding the loci contributing to CD.

Bone in celiac disease.

Chronic inflammation and malabsorption in celiac disease (CD) can cause bone metabolism alterations and bone mineral loss in children and adults. Bone status before and after gluten-free diet, epidemiology of fractures, and possible treatment options for CD-related osteoporosis are presented. Controversial aspects of this complication of CD are discussed. The relationship between bone derangements and celiac disease (CD) was recognized almost 50 years ago, but many questions are still open. We are now aware that osteoporosis is a relatively frequent atypical presentation of CD, especially in adults, and that undiagnosed CD can be the cause of osteoporosis and related fractures. Chronic inflammatory intestinal diseases, including CD, can affect bone and mineral metabolism because of alterations in both systemic and local regulatory factors. The pathogenetic processes are still controversial, but two main mechanisms seem to be involved: intestinal malabsorption and the presence of chronic inflammation. This review analyzes the published data on bone involvement in children, adolescents, and adults either before or after a gluten-free diet. Special attention is paid to the epidemiology of fractures in celiac patients, considering that fractures are a major complication of osteoporosis and an important problem in the management of a chronic disease like CD. The usefulness of screening osteoporotic patients systematically for CD is still an open question, but some rules can be given. Finally, the current treatment options for children and adults are discussed. Recommendations for future clinical research are proposed.

Coeliac disease: a histological follow-up study.

AIMS: To assess the histological response to a gluten-free diet (GFD) in a series of coeliac patients in clinical remission, of different ages and with varying degrees of mucosal damage at diagnosis. METHODS AND RESULTS: Biopsy samples from 249 coeliac patients (F 165, M 84) were analysed basally and after clinical and biochemical remission following a GFD. All patients showed an improvement in mucosal findings after starting a GFD, but complete histological normalization was observed in 74.1% of paediatric cases (diagnosed before 14 years of age) and in only 17.5% of adults. Statistical analysis showed that sex, the clinical picture at diagnosis and the length of time between biopsy at the time of diagnosis and on a GFD were not related to histological normalization. In contrast, the age at diagnosis was statistically significantly related to it (P < 0.0001). In addition, the presence/absence of Helicobacter pylori was independent of the normalization of the duodenal mucosa. CONCLUSIONS: In clinical practice the criteria for diagnosis of coeliac disease are sufficiently standardized, whereas for follow-up they are less well defined. We suggest that in order to compare the results from different studies, it should be stated whether remission after treatment is based on clinical or histological criteria or both.

Searching for coeliac disease in patients with non-alcoholic fatty liver disease.

BACKGROUND: A non-negligible percentage of patients with non-alcoholic fatty liver disease, a leading cause of hepatic progressive disorder related to insulin resistance, have no metabolic risk factors, and abnormal intestinal permeability has been suggested to be involved in the pathogenesis of the liver damage. Coeliac disease, a curable disorder characterised by inflammatory mucosal damage, may show hepatic histological features similar to steatohepatitis. Conflicting data have been reported on the prevalence of coeliac disease in non-alcoholic steatohepatitis. AIM: To search for coeliac disease in a series of patients with non-alcoholic fatty liver disease by screening with anti-tissue transglutaminase and anti-endomysium antibodies. PATIENTS AND METHODS: Fifty-nine consecutive patients with hypertransaminasemia and non-alcoholic fatty liver disease, 38 (64%) with steatohepatitis. Anti-endomysium antibodies were assayed by indirect immunofluorescence, IgA anti-tissue transglutaminase by ELISA. Patients who tested positive underwent HLA DQ typing and endoscopy. RESULTS: Tissue transglutaminase antibodies were positive in six (10%) patients and anti-endomysium in two (3.4%); only two (3.4%), positive for both anti-endomysium positive and anti-transglutaminase, resulted to have coeliac disease based on histological findings. After 6 months of gluten-free diet, liver enzymes normalised. CONCLUSIONS: The prevalence of silent coeliac disease is 3.4% in patients with non-alcoholic fatty liver. The inclusion of anti-endomysium antibodies test in studying patients with non-alcoholic fatty liver and persistent biochemical abnormalities has to be taken into account, since positivity for tissue transglutaminase antibodies, in the absence of confirmatory anti-endomysium antibodies, is not sufficient to perform diagnostic endoscopy.

Long-term remission in patients with dermatitis herpetiformis on a normal diet.

BACKGROUND: A life-long gluten-free diet is the treatment of choice for dermatitis herpetiformis, which is considered to be coeliac disease of the skin. OBJECTIVES: To investigate the effects on long-term remission of dermatitis herpetiformis in patients who underwent a gluten challenge and subsequently reintroduced dietary gluten. PATIENTS AND METHODS: We studied 38 patients (14 male and 24 female) with biopsy-confirmed dermatitis herpetiformis. They had followed a gluten-free diet for a mean of 8 years, achieving clinical remission and intestinal normalization. The patients were asked to reintroduce gluten in their diet and agreed to undergo skin and intestinal biopsies during the follow-up. RESULTS: Of the 38 patients abandoning a gluten-free diet, 31 reported the onset of rash within an average of 2 months. Seven subjects (three males, mean age 15 years at challenge) experienced no clinical or histological relapses (median follow-up 12 years), and lost IgA immunoglobulin from the skin. The two series of patients differed in terms of age at diagnosis (mean age: 26.6 vs. 6 years), the use of dapsone (one of 31 vs. four of seven) and adherence to the gluten-free diet (strict compliance in 26 of 31 vs. none of seven). CONCLUSIONS: Our data suggest that the ingestion of small doses of gluten in childhood and/or the use of an anti-inflammatory drug may modify the immunological response inducing immune tolerance. We report long-term clinical and histological remissions in seven patients with dermatitis herpetiformis after the reintroduction of dietary gluten.

Bread wheat gliadin cytotoxicity: a new three-dimensional cell model.

BACKGROUND: In an attempt to clarify the role of gliadin toxicity in the pathogenesis of gluten intolerance (celiac disease), previous in vitro studies have been based on two-dimensional human cell cultures. However, the specific morphological and biochemical properties of in vivo tissue are better maintained in three-dimensional cell cultures (multicellular spheroids, MCS). The aim of this study was to develop a three-dimensional in vitro model to investigate the effects of gliadin on epithelial cells and broaden our understanding of the early tissue damage occurring in celiac disease. METHODS: The three-dimensionally growing Lovo cell line was exposed to increasing concentrations of peptic-tryptic-digested bread wheat gliadin (from 125 to 1000 microg/mL) for 7 days in order to evaluate cell viability (colony-forming assay), and at the standard concentration of 500 microg/mL for 7 days in order to evaluate MCS diameters, volumes and cell morphology using light and electron microscopy. RESULTS: In comparison with the controls, the cell viability of the gliadin-treated MCS was significantly reduced (20-80%), but there was no difference in size. Various degrees of cell damage (autophagic vacuoles and intra-cytoplasmic lipid-like droplets) were detected by both light and electron microscopy. CONCLUSION: This is the first study investigating the effects of gliadin on MCS. Lovo MCS seem to be responsive to gliadin exposure, thus confirming previous results obtained using two-dimensional cell cultures. The data suggest that three-dimensional cell cultures may be useful in broadening our understanding of some of the early effects of gliadin peptides on epithelial cells.

Bone and celiac disease.

Celiac disease is an intestinal disease due to an abnormal immuno-mediated response to gluten and other peptides from different cereals in genetically susceptible subjects. Several systemic alterations, including bone alterations, may be present in affected subjects. Once considered rare, it is now known to be quite frequent in both Europe and North America, as the recent availability of specific serological markers has drastically changed our perspective on its prevalence. The diagnosis of celiac disease may be very difficult because the clinical picture is highly variable and the characteristic intestinal signs and symptoms may be completely absent. Among the extra-intestinal alterations, bone mass decrease and bone metabolism derangement are frequently present and can be the only signs of an otherwise silent celiac disease. Clinical and epidemiological data are now plentiful but no conclusive data on the pathogenesis of bone involvement in celiac disease are available yet. Bone alterations were once thought to derive from calcium and vitamin D deficiency secondary to simple intestinal malabsorption, but now a more complex interaction between cytokines and local/systemic factors influencing bone formation and reabsorption is envisaged, Also, there is now substantial evidence supporting a lifelong gluten-free diet as the first-choice therapy for celiac disease, and as far as we know, this is the only effective measure to restore bone metabolism to an apparent normality. In the young, an early-started gluten-free diet can even lead to a satisfactory recovery of bone mass. In adults, however, there is no spontaneous recovery, and there are no conclusive data on the efficacy of standard therapies for osteoporosis in reducing the fracture risk. For these reasons, we feel that a review of the clinical findings on bone problems in celiac disease may be useful for both gastroenterologists and osteoporosis specialists.

In vitro cytotoxic effect of bread wheat gliadin on the LoVo human adenocarcinoma cell line.

The pathogenesis of celiac disease is not completely understood but, although the initial step of the process is still unclear, an altered immune response seems to play a major role. Previous studies of the biological properties of gliadin have highlighted its cytotoxic effects, and the aim of this study was to develop an in vitro technique to study them. The LoVo (human colon adenocarcinoma) cell line grown in two-dimensional cultures was exposed to different concentrations of digested bread wheat gliadin (62, 125, 250, 500 and 750 microg/ml) for 48 h, after which cell growth and oxidative balance (the content of reduced glutathione (GSH), and peroxidase, transferase and reductase activity) was evaluated. Other food proteins were used as controls. Our data revealed a statistically significant inhibition of cell growth in proportion to the gliadin concentration (from 26 to 100%), combined with a decrease in GSH content (-38% at 500 microg/ml) and reduced enzymatic activity (-30% at 500 microg/ml). The controls did not show any noxious effect. Our results confirm the usefulness of LoVo cells in evaluating gliadin cytotoxicity and that they can be used to investigate the biological properties of gliadin.

High frequency of anti-endomysial reactivity in candidates to heart transplant.

BACKGROUND: A possible link between coeliac disease and dilated cardiomyopathy has recently been suggested. AIMS: . To assess the frequency of anti-endomysial antibodies, the marker for coeliac disease, in patients with different forms of heart failure, and to establish the clinical features of those endomysial antibody positive. SUBJECTS AND METHODS: . A total of 642 consecutive patients entering the waiting list for heart transplantation from 1995 through 1997 were studied. The prevalence of endomysial IgA antibodies, determined by indirect immunofluorescence, was compared to that observed in three surveys conducted in the Italian general population. RESULTS: Of the 642 patients, 12 (1.9%; 95% confidence interval 0.97-3.2) resulted endomysial antibody positive, versus 34/9,720 healthy controls (0.35%; 95% confidence interval, 0.23-0.47), accounting for a relative risk of 5.3 (95% confidence interval, 2.8-10.3). Anti-endomysial antibodies were found in 6/275 patients with dilated cardiomyopathy and 6/367 with other forms of heart failure (2.2% versus 1.6%; 95% confidence interval 0.8-4.7 and 0.6-3.5), with no statistical difference. The 12 endomysial antibody positive patients were leaner (body mass index, 22.0 +/- 1.9 vs 24.2 +/- 3. 1, p<0. 05) than 36 seronegative patients matched for baseline demographics and aetiology of cardiomyopathy No differences were observed as regards clinical, biochemical and echocardiographic features, mortality in waiting list and 2-year post-transplant survival. CONCLUSIONS: Patients with end-stage heart failure are at increased risk for coeliac disease as compared to the general population.