Coeliac disease is an inflammatory disorder of the small intestine with an autoimmune component and strong heritability. Genetic studies have confirmed strong association to HLA and identified 39 nonHLA risk genes, mostly immune-related. Over 50% of the disease-associated single nucleotide polymorphisms are correlated with gene expression. Most of the coeliac disease-associated regions are shared with other immune-related diseases, as well as with metabolic, haematological or neurological traits, or cancer. We review recent progress in the genetics of coeliac disease and describe the pathways these genes are in, the functional consequences of the associated markers on gene expression and the genes shared between coeliac disease and other traits.

OBJECTIVE:A possible association of celiac disease with psychiatric and psychological disturbances such as attention-deficit/hyperactivity disorder (ADHD) has been reported repeatedly. The objective of this study was to observe whether a gluten-free diet could alleviate the behavioral symptoms in patients with celiac disease and ADHD.

METHOD:Sixty-seven subjects aged 7 to 42 years (mean = 11.4 years) with ADHD were enrolled in the study in South Tyrol, Italy, from 2004 to 2008. Hypescheme, an operational criteria checklist that incorporates DSM-IV and ICD-10 criteria, was used to assess ADHD-like symptomatology. Additionally, blood serum levels of all subjects were assessed for possible celiac disease by examining antigliadine and antiendomysium antibodies. A gluten-free diet was initiated for at least 6 months in celiac disease-positive patients with ADHD.

RESULTS:Of the 67 patients with ADHD, 10 were positive for celiac disease. After initiation of the gluten-free diet, patients or their parents reported a significant improvement in their behavior and functioning compared to the period before celiac diagnosis and treatment, which was evident in the overall mean score on the Hypescheme questionnaire (t = 4.22, P = .023).

CONCLUSIONS:Celiac disease is markedly overrepresented among patients presenting with ADHD. A gluten-free diet significantly improved ADHD symptoms in patients with celiac disease in this study. The results further suggest that celiac disease should be included in the ADHD symptom checklist.

CASE REPORT: A 29-year-old wheelchair-bound woman was presented to us by the gastroenterologist with suspected osteomalacia. She had lived in the Netherlands all her life and was born of Moroccan parents. Her medical history revealed iron deficiency, growth retardation, and celiac disease, for which she was put on a gluten-free diet. She had progressive bone pain since 2 years, difficulty with walking, and about 15 kg weight loss. She had a short stature, scoliosis, and pronounced kyphosis of the spine and poor condition of her teeth. Laboratory results showed hypocalcemia, an immeasurable serum 25-hydroxyvitamin D level, and elevated parathyroid hormone and alkaline phosphatase levels. Spinal radiographs showed unsharp, low contrast vertebrae. Bone mineral density measurement at the lumbar spine and hip showed a T-score of -6.0 and -6.5, respectively. A bone scintigraphy showed multiple hotspots in ribs, sternum, mandible, and long bones. A duodenal biopsy revealed villous atrophy (Marsh 3C) and positive antibodies against endomysium, transglutaminase, and gliadin, compatible with active celiac disease. A bone biopsy showed severe osteomalacia but normal bone volume. She was treated with calcium intravenously and later orally. Furthermore, she was treated with high oral doses of vitamin D and a gluten-free diet. After a few weeks of treatment, her bone pain decreased, and her muscle strength improved.

DISCUSSION: In this article, the pathophysiology and occurrence of osteomalacia as a complication of celiac disease are discussed. Low bone mineral density can point to osteomalacia as well as osteoporosis.

ABSTRACT: Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients.

BACKGROUND:Celiac disease (CD) is an autoimmune disorder, characterized by the presence of gastrointestinal and multisystem symptoms, which occasionally mimic those of Irritable Bowel Syndrome (IBS) and Fibromyalgia Syndrome (FMS). To assess the effectiveness of a Gluten-Free Diet (GFD) in seven adult female screening-detected CD subjects, categorized as severe IBS and FMS patients.

METHODS:All subjects showed villous atrophy in duodenal biopsies, were HLA-DQ2/DQ8-positive, and fulfilled the Rome III and ACR 1990 criteria respectively for IBS and FMS classification. GFD effectiveness was assessed at baseline and after 1 year, examining the score changes in the Tender Points (TPs) test, Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ), Short Form Health Survey (SF-36), Visual Analogue Scales (VAS) for gastrointestinal complaints, pain and tiredness, drug prescriptions and tissue-Trans-Glutaminase (tTG) serum levels.

RESULTS:At baseline, all patients had poor Quality of Life and VAS scores, a high number of TPs and drug prescriptions, and increased tTG levels. After 1 year of GFD, all outcome measures significantly improved, with a decrease of 51-60% in TPs, FIQ, HAQ, and VAS scales, and in the number of prescribed drugs, accompanied by an increase of 48-60% in SF-36 Physical and Mental Component Summary scores, and a decrease of tTG to normal values.

CONCLUSION:Results of this pilot study show that the adherence to a GFD by CD-related IBS/FMS patients can simultaneously improve CD and IBS/FMS symptoms, and indicate the merit of further research on a larger cohort.

Coeliac disease, epilepsy and cerebral calcifications (CEC) syndrome is a rare clinical condition. One hundred and seventy-one patients have been reported in the literature. Patients are mostly from Italy, Spain, and Argentina, suggesting a geographically restricted condition. Epilepsy is more frequently characterized by occipital seizures. It may be benign or drug-resistant, sometime evolving into severe epileptic encephalopathy. Gluten free diet (GFD) efficacy seems to be inversely related to the duration of epilepsy and the young age of the patient. Patients with cerebral calcifications (CC) and coeliac disease (CD) without epilepsy are considered as having an incomplete form of CEC syndrome. Some patients with epilepsy and CC without CD are supposed to have a CEC syndrome with silent or latent CD. Whether CEC syndrome is a genetic condition, or whether epilepsy and/or CC are a consequence of an untreated CD is unknown yet. Since histopathological findings seem to be the expression of vascular calcified malformation, CEC syndrome may be considered a genetically determined entity, such as a type of Sturge-Weber-like phacomatosis. Moreover, CEC, as well as CD, is associated with HLA-DQ2 and HLA-DQ8 phenotype and genotype. The progressive growth and late occurrence of CC before beginning a GFD, the demonstration of anti-gliadin antibodies in the cerebro-spinal fluid and the association with HLA class II genes, suggest that an immune reaction originating from the jejunal mucosa, triggered by gliadin in gluten intolerance predisposed subjects (HLA phenotype) may be responsible for seizures and CC. Moreover, a long-lasting untreated CD folic acid deficiency may cause calcifications. Probably, CEC is considered a genetic, non-inherited, ethnically and geographically restricted syndrome associated with environmental factors.

Dramatic improvement of parkinsonian symptoms after gluten-free diet introduction in a patient with silent celiac disease.

BACKGROUND AND AIM:In celiac disease (CD) the role of a gluten-free diet (GFD) on gastroesophageal reflux disease-related symptoms (GERD-rs) is unclear. The aim of this study was to establish the recurrence of GERD-rs, in CD patients with nonerosive reflux disease (NERD).

METHODS:From a total of 105 adult CD patients observed, 29 who presented with the NERD form were enrolled in the study. Thirty non-CD patients with NERD were studied as controls. Recurrence of GERD-rs was clinically assessed at 6, 12, 18, and 24 months follow-up (FU) after withdrawal of initial proton-pump inhibitor (PPI) treatment for 8 weeks.

RESULTS:GERD-rs were resolved in 25 (86.2%) CD patients and in 20 (66.7%) controls after 8 weeks of PPI treatment. In the CD group, recurrence of GERD-rs was found in five cases (20%) at 6 months but in none at 12, 18, and 24 months while in the control group recurrence was found in six of 20 controls (30%), in another six (12/20, 60%), in another three (15/20, 75%), and in another two (17/20, 85%) at 6, 12, 18, and 24 months FU respectively.

CONCLUSIONS:The present study is the first to have evaluated the effect of a GFD in the nonerosive form of GERD in CD patients, by means of clinical long-term follow-up, suggesting that GFD could be a useful approach in reducing GERD symptoms and in the prevention of recurrence.

Celiac disease, eosinophilic esophagitis, and urticaria are 3 manifestations of food allergy with different pathogenic mechanisms. We report the case of a 2-year-old child with digestive symptoms, slow growth, and severe asthma. The results of skin prick tests were positive to several foods. Endoscopy revealed eosinophilic esophagitis and celiac disease. Treatment consisted of a gluten-free diet and a 1-month course of oral corticosteroids. Endoscopy and biopsy findings were normal at 5 years of age. A gluten-free diet is the basis of treatment of celiac disease, but the role of an elimination diet in eosinophilic esophagitis is not well established. Our patient also developed urticaria when exposed to milk and egg.We present, to our knowledge, the first report of a patient with celiac disease, eosinophilic esophagitis, and immediate-type immunoglobulin E-mediated food allergy.

BACKGROUND & AIMS:Celiac disease (CD) patients often complain of symptoms consistent with gastroesophageal reflux disease (GERD). We aimed to assess the prevalence of GERD symptoms at diagnosis and to determine the impact of the gluten-free diet (GFD).

METHODS:We evaluated 133 adult CD patients at diagnosis and 70 healthy controls. Fifty-three patients completed questionnaires every 3 months during the first year and more than 4 years after diagnosis. GERD symptoms were evaluated using a subdimension of the Gastrointestinal Symptoms Rating Scale for heartburn and regurgitation domains.

RESULTS:At diagnosis, celiac patients had a significantly higher reflux symptom mean score than healthy controls (P<.001). At baseline, 30.1% of CD patients had moderate to severe GERD (score>3) compared with 5.7% of controls (P<.01). Moderate to severe symptoms were significantly associated with the classical clinical presentation of CD (35.0%) compared with atypical/silent cases (15.2%; P<.03). A rapid improvement was evidenced at 3 months after initial treatment with a GFD (P<.0001) with reflux scores comparable to healthy controls from this time point onward.

CONCLUSIONS:GERD symptoms are common in classically symptomatic untreated CD patients. The GFD is associated with a rapid and persistent improvement in reflux symptoms that resembles the healthy population.

BACKGROUND:It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of persons with autism. If this is the case, diets free of gluten and /or casein should reduce the symptoms associated with autism.

OBJECTIVES:To determine the efficacy of gluten- and/or casein- free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism.

SEARCH STRATEGY:Electronic searching of abstracts from the Cochrane Library (Issue 3, 2003), PsycINFO (1971- May 2003), EMBASE (1974- May 2003), CINAHL (1982- May 2003), MEDLINE (1986- May 2003), ERIC (1965-2003), LILACS (to 2003) and the specialist register of the Cochrane Complementary Medicine Field (January 2004). Review bibliographies were also examined to identify potential trials.

SELECTION CRITERIA:All randomised controlled trials involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with autistic spectrum disorder.

DATA COLLECTION AND ANALYSIS:Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. The authors independently selected the relevant studies from the reports identified in this way. As only one trial fitted the inclusion criteria, no meta-analysis is currently possible and data are presented in narrative form.

MAIN RESULTS:The one trial included reported results on four outcomes. Unsurprisingly in such a small-scale study, the results for three of these outcomes (cognitive skills, linguistic ability and motor ability) had wide confidence intervals that spanned the line of nil effect. However, the fourth outcome, reduction in autistic traits, reported a significant beneficial treatment effect for the combined gluten- and casein- free diet.

REVIEWERS' CONCLUSIONS:This is an important area of investigation and large scale, good quality randomised controlled trials are needed.

Gluten exclusion (protein complex present in many cereals) has been proposed as an option for the prevention of diseases other than coeliac disease. However, the effects of gluten-free diets on obesity and its mechanisms of action have not been studied. Thus, our objective was to assess whether gluten exclusion can prevent adipose tissue expansion and its consequences. C57BL/6 mice were fed a high-fat diet containing 4.5% gluten (Control) or no gluten (GF). Body weight and adiposity gains, leukocyte rolling and adhesion, macrophage infiltration and cytokine production in adipose tissue were assessed. Blood lipid profiles, glycaemia, insulin resistance and adipokines were measured. Expression of the PPAR-α and γ, lipoprotein lipase (LPL), hormone sensitive lipase (HSL), carnitine palmitoyl acyltransferase-1 (CPT-1), insulin receptor, GLUT-4 and adipokines were assessed in epidydimal fat. Gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion. These results were associated with up-regulation of PPAR-α, LPL, HSL and CPT-1, which are related to lipolysis and fatty acid oxidation. There was an improvement in glucose homeostasis and pro-inflammatory profile-related overexpression of PPAR-γ. Moreover, intravital microscopy showed a lower number of adhered cells in the adipose tissue microvasculature. The overexpression of PPAR-γ is related to the increase of adiponectin and GLUT-4. Our data support the beneficial effects of gluten-free diets in reducing adiposity gain, inflammation and insulin resistance. The data suggests that diet gluten exclusion should be tested as a new dietary approach to prevent the development of obesity and metabolic disorders.

Eight adult female patients suffering from abdominal pain and chronic diarrhea which was often incapacitating and frequently nocturnal, had dramatic relief on a gluten-free diet and return of symptoms after gluten challenge. Previous nonspecific measures and a milk-free diet were ineffective. Multiple jejunal biopsies showed minor, but significant changes in cellularity which returned to normal on the gluten-free diet. Apart from a slight increase in jejunal cellularity, no immunological abnormalities were found after gluten challenge. Steatorrhea or other biochemical defects, common in celiac disease, were not found. It was concluded that these patients had a gluten-sensitive diarrhea, but had no evidence of celiac disease.

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.

Epidermolysis bullosa (EB) is a rare inherited genetic disease characterized by an abnormal response of the skin and mucosa to mechanical trauma. Dystrophic EB (DEB) is very often associated with many extra cutaneous complications. Those complications involve either epithelial associated tissues or other organs. In particular, several renal complications have been described for DEB in the recessive form, such as amyloidosis, post-infection glomerulonephritis, upper and lower urinary tract obstruction and IgA-Nephropathy (IgAN). In the cases reported below we have two patients diagnosed with DEB that showed compromised renal function and proteinuria. The switch of the normal diet toward a gluten free diet resulted beneficial for both patients, since renal function was rescued and proteinuria cured. Moreover, a general health status improvement was recognised, given that nutritional condition was ameliorated and bone growing enhanced. Furthermore, in both patients the presence of autoantibodies anti-COL7 indicating an autoimmune form of the disease. Therefore, patients received low doses of betametasone useful to reduce inflammatory state and to control immune system function. In conclusion, our results prompt us to hypothesized that in these patients, due to the fragility of the intestinal mucosa, the absence in the diet of gluten may be beneficial.

Celiac disease (CD) is Gluten sensitive enteropathy with a wide spectrum of severity and protean clinical manifestations. Patients with atypical (non-diarrhoeal) presentations are missed as the diagnosis of Celiac Disease is not considered. We present three young girls (ages 18, 19, 23 at presentation) who were admitted to our hospital as intractable seizures. All had low serum calcium, features of rickets/osteomalacia and anaemia. This prompted us to consider malabsorption due to CD. The diagnosis of CD was confirmed by serologic tests (IgA transglutaminase and IgG antigliadin antibodies) and biopsy of the duodenum. In all patients gluten free diet not only provided drug free control of seizures but also helped correct other features of malabsorption like hypocalcaemia and anaemia as the primary pathology behind these symptoms was corrected. We wish to highlight that hypocalcaemia of CD which may present as intractable seizures can be treated only by treating CD with gluten free diet and not by oral vitamin D and Calcium alone.

Jejunal biopsies in 33 patients with troublesome recurrent aphthous ulceration seen over one year showed eight with flat mucosa compatible with coeliac disease. All remitted completely on a gluten-free diet, both clinically and haematologically, and the aphthous ulceration did not recur. Gluten sensitivity is aetiologically important in patients with recurrent aphthous ulceration and flat mucosa, and patients with recurrent ulceration should undergo jejunal biopsy.

We report a case of a three-and-a-half-year-old boy, who presented with poor general condition, stunted growth, had the presence of nail clubbing, persistent cough and frequent diarrhoea. Persistent iron deficiency anaemia without signs of haemolysis suggested Lane-Hamilton syndrome (LHS) which is or/is an extremely rare combination of idiopathic pulmonary haemosiderosis (IPH) and celiac disease (CD), although both diseases are immunologically mediated and the pathogenetic link between them is not clear. We have now 3 years of follow-up on gluten-free diet (GFD), resulting in a gradual recovery of the abnormal laboratory results in combination with an improving growth. Clinically, he is asymptomatic without any additional treatment. Our case illustrates that CD should be specifically looked for in patients with IPH, especially those in whom the severity of anaemia is disproportionate to the IPH symptoms. Both diseases may benefit from a GFD.

Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC),significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of T1D by changing the gut microbiome.

A 36 year old woman presented with malabsorption and macroamylasemia. The macroamylase was characterized and shown to be a complex of pancreatic amylase and immunoglobulin A(IgA). The patient had the clinical and histologic features of adult celiac disease, and responded to a gluten-free diet. The macroamylase complex disappeared from the serum after gluten withdrawal, a hitherto unreported finding in the syndrome of malabsorption and hyperamylasemia.