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1.  Testing for gluten-related disorders in clinical practice: The role of serology in managing the spectrum of gluten sensitivity 
Immunoglobulin A tissue transglutaminase is the single most efficient serological test for the diagnosis of celiac disease. It is well known that immunoglobulin A tissue transglutaminase levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with celiac disease. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Antigliadin tests are no longer recommended for the diagnosis of classical celiac disease. However, our understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. Studies are needed to determine the clinical utility of antigliadin serology in the diagnosis of gluten sensitivity.
PMCID: PMC3088693  PMID: 21523259
Antigliadin antibodies; Antitissue transglutaminase; Celiac disease; Diagnosis; Gluten intolerance; Serology
2.  Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity 
BMC Gastroenterology  2014;14:26.
Background
Non-celiac gluten sensitivity is a syndrome characterized by gastrointestinal and extra-intestinal symptoms occurring in a few hours/days after gluten and/or other wheat protein ingestion and rapidly improving after exclusion of potential dietary triggers. There are no established laboratory markers for non-celiac gluten sensitivity, although a high prevalence of first generation anti-gliadin antibodies of IgG class has been reported in this condition. This study was designed to characterize the effect of the gluten-free diet on anti-gliadin antibodies of IgG class in patients with non-celiac gluten sensitivity.
Methods
Anti-gliadin antibodies of both IgG and IgA classes were assayed by ELISA in 44 non-celiac gluten sensitivity and 40 celiac disease patients after 6 months of gluten-free diet.
Results
The majority of non-celiac gluten sensitivity patients (93.2%) showed the disappearance of anti-gliadin antibodies of IgG class after 6 months of gluten-free diet; in contrast, 16/40 (40%) of celiac patients displayed the persistence of these antibodies after gluten withdrawal. In non-celiac gluten sensitivity patients anti-gliadin antibodies IgG persistence after gluten withdrawal was significantly correlated with the low compliance to gluten-free diet and a mild clinical response.
Conclusions
Anti-gliadin antibodies of the IgG class disappear in patients with non-celiac gluten sensitivity reflecting a strict compliance to the gluten-free diet and a good clinical response to gluten withdrawal.
doi:10.1186/1471-230X-14-26
PMCID: PMC3926852  PMID: 24524388
Anti gliadin antibodies; Non-celiac gluten sensitivity; Celiac disease
3.  Five-year follow-up of 263 cases of functional bowel disorder 
AIM: To determine the mortality associated with functional bowel disorders (FBDs) and their possible relationship with organic bowel disease.
METHODS: Patients who satisfied the Rome III criteria for FBD (retrospective diagnosis) were followed up by telephone interview and/or outpatient review at 5 years after their first attendance. The patients were divided into the following groups: irritable bowel syndrome, functional abdominal bloating, functional constipation, functional diarrhea and unspecified FBD. The survival of the FBD patients overall and of those with each FBD were compared with data obtained from the Guangzhou population in 2005. The incidences of colonic cancer overall and for each FBD were compared with data from the Chinese population obtained from 56 cancer registries in 19 provinces of the country in 2008.
RESULTS: Two hundred and sixty-three patients were followed-up. Five patients died, which was not significantly different from the expected survival rate. No differences in mortality among the FBDs were found. There were nine cases of organic bowel disease: three colonic cancers and six colonic polyps. The incidence of colonic cancer in FBD patients was higher than that in the general Chinese population (0.23% vs 0.03%, P < 0.05). There were significant differences in the incidence of colonic cancer among the FBDs (0/134, 0/24, 2/29, 1/66, 0/10, respectively, P < 0.05); functional constipation was the most common. The incidence of colonic polyps was similar among the FBDs. The baseline age of patients who died was greater than that of those who survived (66.60 ± 6.84 years vs 45.14 ± 10.34 years, P < 0.05). The baseline age of patients who had colonic cancer or polyps during follow-up was greater than that of those without colonic cancer or polyps (60.33 ± 1.53 years vs 45.38 ± 10.62 years; 54.50 ± 6.47 years vs 45.34 ± 10.68 years, P < 0.05).
CONCLUSION: FBDs do not increase the risk of death. The incidence of colonic cancer in patients with FBDs may be increased, especially in those with functional constipation and in the elderly.
doi:10.3748/wjg.v19.i9.1466
PMCID: PMC3602507  PMID: 23539637
Functional bowel disorders; Follow-up; Mortality; Colonic cancer; Colonic polyps
4.  The Immune System in Irritable Bowel Syndrome 
The potential relevance of systemic and gastrointestinal immune activation in the pathophysiology and symptom generation in the irritable bowel syndrome (IBS) is supported by a number of observations. Infectious gastroenteritis is the strongest risk factor for the development of IBS and increased rates of IBS-like symptoms have been detected in patients with inflammatory bowel disease in remission or in celiac disease patients on a gluten free diet. The number of T cells and mast cells in the small and large intestine of patients with IBS is increased in a large proportion of patients with IBS over healthy controls. Mediators released by immune cells and likely from other non-immune competent cells impact on the function of enteric and sensory afferent nerves as well as on epithelial tight junctions controlling mucosal barrier of recipient animals, isolated human gut tissues or cell culture systems. Antibodies against microbiota antigens (bacterial flagellin), and increased levels of cytokines have been detected systemically in the peripheral blood advocating the existence of abnormal host-microbial interactions and systemic immune responses. Nonetheless, there is wide overlap of data obtained in healthy controls; in addition, the subsets of patients showing immune activation have yet to be clearly identified. Gender, age, geographic differences, genetic predisposition, diet and differences in the intestinal microbiota likely play a role and further research has to be done to clarify their relevance as potential mechanisms in the described immune system dysregulation. Immune activation has stimulated interest for the potential identification of biomarkers useful for clinical and research purposes and the development of novel therapeutic approaches.
doi:10.5056/jnm.2011.17.4.349
PMCID: PMC3228974  PMID: 22148103
Abdominal pain; Immune system; Irritable bowel syndrome; Mast cells
5.  Complementary and alternative medicine use and cost in functional bowel disorders: A six month prospective study in a large HMO 
Background
Functional Bowel Disorders (FBD) are chronic disorders that are difficult to treat and manage. Many patients and doctors are dissatisfied with the level of improvement in symptoms that can be achieved with standard medical care which may lead them to seek alternatives for care. There are currently no data on the types of Complementary and Alternative Medicine (CAM) used for FBDs other than Irritable Bowel Syndrome (IBS), or on the economic costs of CAM treatments. The aim of this study is to determine prevalence, types and costs of CAM in IBS, functional diarrhea, functional constipation, and functional abdominal pain.
Methods
1012 Patients with FBD were recruited through a health care maintenance organization and followed for 6 months. Questionnaires were used to ascertain: Utilization and expenditures on CAM, symptom severity (IBS-SS), quality of life (IBS-QoL), psychological distress (BSI) and perceived treatment effectiveness. Costs for conventional medical care were extracted from administrative claims.
Results
CAM was used by 35% of patients, at a median yearly cost of $200. The most common CAM types were ginger, massage therapy and yoga. CAM use was associated with female gender, higher education, and anxiety. Satisfaction with physician care and perceived effectiveness of prescription medication were not associated with CAM use. Physician referral to a CAM provider was uncommon but the majority of patients receiving this recommendation followed their physician's advice.
Conclusion
CAM is used by one-third of FBD patients. CAM use does not seem to be driven by dissatisfaction with conventional care. Physicians should discuss CAM use and effectiveness with their patients and refer patients if appropriate.
doi:10.1186/1472-6882-8-46
PMCID: PMC2499988  PMID: 18652682
6.  Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders 
Nutrients  2013;5(10):3839-3853.
Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.
doi:10.3390/nu5103839
PMCID: PMC3820047  PMID: 24077239
gluten sensitivity; celiac disease; wheat allergy; gluten-related disorders; gluten-free diet
7.  Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity 
BMC Medicine  2011;9:23.
Background
Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders.
Methods
CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity.
Results
Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293).
Conclusions
This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.
doi:10.1186/1741-7015-9-23
PMCID: PMC3065425  PMID: 21392369
8.  Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease 
BMC Gastroenterology  2011;11:129.
Background
Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient.
We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration.
Methods
Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined.
Results
Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients.
Conclusions
Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis.
doi:10.1186/1471-230X-11-129
PMCID: PMC3240817  PMID: 22115041
9.  Functional bowel disorders and functional abdominal pain 
Gut  1999;45(Suppl 2):II43-II47.
The Rome diagnostic criteria for the functional bowel disorders and functional abdominal pain are used widely in research and practice. A committee consensus approach, including criticism from multinational expert reviewers, was used to revise the diagnostic criteria and update diagnosis and treatment recommendations, based on research results. The terminology was clarified and the diagnostic criteria and management recommendations were revised. A functional bowel disorder (FBD) is diagnosed by characteristic symptoms for at least 12 weeks during the preceding 12 months in the absence of a structural or biochemical explanation. The irritable bowel syndrome, functional abdominal bloating, functional constipation, and functional diarrhea are distinguished by symptom-based diagnostic criteria. Unspecified FBD lacks criteria for the other FBDs. Diagnostic testing is individualized, depending on patient age, primary symptom characteristics, and other clinical and laboratory features. Functional abdominal pain (FAP) is defined as either the FAP syndrome, which requires at least six months of pain with poor relation to gut function and loss of daily activities, or unspecified FAP, which lacks criteria for the FAP syndrome. An organic cause for the pain must be excluded, but aspects of the patient's pain behavior are of primary importance. Treatment of the FBDs relies upon confident diagnosis, explanation, and reassurance. Diet alteration, drug treatment, and psychotherapy may be beneficial, depending on the symptoms and psychological features.


Keywords: functional bowel disorder; functional constipation; functional diarrhea; irritable bowel syndrome; functional abdominal pain; functional abdominal bloating; Rome II
PMCID: PMC1766683  PMID: 10457044
10.  Monitoring of gluten-free diet compliance in celiac patients by assessment of gliadin 33-mer equivalent epitopes in feces123 
Background: Certain immunotoxic peptides from gluten are resistant to gastrointestinal digestion and can interact with celiac-patient factors to trigger an immunologic response. A gluten-free diet (GFD) is the only effective treatment for celiac disease (CD), and its compliance should be monitored to avoid cumulative damage. However, practical methods to monitor diet compliance and to detect the origin of an outbreak of celiac clinical symptoms are not available.
Objective: We assessed the capacity to determine the gluten ingestion and monitor GFD compliance in celiac patients by the detection of gluten and gliadin 33-mer equivalent peptidic epitopes (33EPs) in human feces.
Design: Fecal samples were obtained from healthy subjects, celiac patients, and subjects with other intestinal pathologies with different diet conditions. Gluten and 33EPs were analyzed by using immunochromatography and competitive ELISA with a highly sensitive antigliadin 33-mer monoclonal antibody.
Results: The resistance of a significant part of 33EPs to gastrointestinal digestion was shown in vitro and in vivo. We were able to detect gluten peptides in feces of healthy individuals after consumption of a normal gluten-containing diet, after consumption of a GFD combined with controlled ingestion of a fixed amount of gluten, and after ingestion of <100 mg gluten/d. These methods also allowed us to detect GFD infringement in CD patients.
Conclusions: Gluten-derived peptides could be sensitively detected in human feces in positive correlation with the amount of gluten intake. These techniques may serve to show GFD compliance or infringement and be used in clinical research in strategies to eliminate gluten immunotoxic peptides during digestion. This trial was registered at clinicaltrials.gov as NCT01478867.
doi:10.3945/ajcn.111.026708
PMCID: PMC3278243  PMID: 22258271
11.  Refractory celiac disease and sprue-like intestinal disease 
Celiac disease is a gluten-dependent small intestinal mucosal disorder that causes malabsorption, often with diarrhea and weight loss. Diagnosis is based on detection of typical biopsy changes in the proximal small bowel, followed by evidence for an unequivocal response to a gluten-free diet. Refractoriness in celiac disease may be due to poor diet compliance, sometimes intentional, or consumption of ubiquitous sources of gluten. Alternatively, the original diagnosis may not be correct (eg., duodenal Crohn’s disease), or a second cause for symptoms may be present (eg., collagenous colitis, functional bowel disorder). In some with recurrent symptoms, a complication may be present (eg., collagenous sprue, small bowel carcinoma, lymphoma). In some, a response to a gluten-free diet can not be unequivocally defined, and more precise historical terms have been used including “sprue-like intestinal disease” or “unclassified sprue”. Although a “wastebasket diagnosis”, these likely represent a heterogeneous group, and some, but not all, may develop lymphoma. Precise definition will be critical in the future as an array of new treatments, including biological agents, may emerge.
doi:10.3748/wjg.14.828
PMCID: PMC2687049  PMID: 18240339
Refractory celiac disease; Refractory sprue; Unclassified sprue; Celiac disease; Intestinal lymphoma; T-cell enteropathy
12.  A Non-Human Primate Model for Gluten Sensitivity 
PLoS ONE  2008;3(2):e1614.
Background and Aims
Gluten sensitivity is widespread among humans. For example, in celiac disease patients, an inflammatory response to dietary gluten leads to enteropathy, malabsorption, circulating antibodies against gluten and transglutaminase 2, and clinical symptoms such as diarrhea. There is a growing need in fundamental and translational research for animal models that exhibit aspects of human gluten sensitivity.
Methods
Using ELISA-based antibody assays, we screened a population of captive rhesus macaques with chronic diarrhea of non-infectious origin to estimate the incidence of gluten sensitivity. A selected animal with elevated anti-gliadin antibodies and a matched control were extensively studied through alternating periods of gluten-free diet and gluten challenge. Blinded clinical and histological evaluations were conducted to seek evidence for gluten sensitivity.
Results
When fed with a gluten-containing diet, gluten-sensitive macaques showed signs and symptoms of celiac disease including chronic diarrhea, malabsorptive steatorrhea, intestinal lesions and anti-gliadin antibodies. A gluten-free diet reversed these clinical, histological and serological features, while reintroduction of dietary gluten caused rapid relapse.
Conclusions
Gluten-sensitive rhesus macaques may be an attractive resource for investigating both the pathogenesis and the treatment of celiac disease.
doi:10.1371/journal.pone.0001614
PMCID: PMC2229647  PMID: 18286171
13.  Prevalence of Anti-deamidated Gliadin Peptide Antibodies in Asian Patients With Irritable Bowel Syndrome 
Background/Aims
Non-celiac gluten sensitivity has been increasingly recognized as a predisposing factor for irritable bowel syndrome (IBS)-like symptoms in Western populations where celiac disease (CD) is relatively common. In Asia where CD is rare, we wish to determine the prevalence of gluten protein associated serology in IBS patients, which has not been formally studied, and its relation to histological and human leukocyte antigen (HLA) markers.
Methods
We reviewed a consecutive cohort of Asian patients with IBS, who had undergone serologic testing for IgA against deamidated gliadin peptide antibodies (IgA DGP) and IgA anti-endomysium antibodies, and who also had duodenal biopsies during clinical workup. In addition, a subset of Chinese patients with positive serology was further tested for HLA-DQ2 and HLA-DQ8.
Results
Of 186 patients, 34 (18%) were positive for IgA DGP; bloating, abdominal pain, belching and diarrhea were the most commonly reported symptoms but diarrhea as the most bothersome symptom was significantly more common in IgA DGP positive patients. Mildly increased intra-epithelial lymphocytes on duodenal biopsy was also more common (29% vs. 9%, P = 0.001). Nine of 21 Chinese patients tested as IgA DGP positive undertook HLA-DQ2/DQ8 testing, with only 2 being positive for HLA-DQ8. All patients with positive IgA DGP reported symptom improvement with gluten withdrawal.
Conclusions
We have described a series of Asian, mainly Chinese, patients with IBS who were tested positive for IgA DGP, and improved on a gluten exclusion diet. We believe this is the first report of non-celiac gluten sensitivity in Asia, a region where CD is uncommon.
doi:10.5056/jnm.2014.20.2.236
PMCID: PMC4015193  PMID: 24840376
Asian; Celiac disease; Gliadin; Gluten sensitive enteropathy; Irritable bowel syndrome
14.  Value of Gluten Patch Test in Diagnosis of Celiac Disease 
Iranian Journal of Pediatrics  2011;21(4):491-496.
Objective
Celiac disease is an intestinal disorder identified by mucus inflammation, villous atrophy and crypt hyperplasia. This disorder can be controlled by elimination of gluten from daily diet. Patients with celiac disease are at greater risk of gastrointestinal malignancy and non-Hodgkin lymphoma than are the general population. This study tries to present the value of gluten patch test for diagnosis of celiac disease.
Methods
In this investigation, the study population was divided into case and control groups. The case group consisted of patients with celiac disease. The control group were patients involved in celiac disease but suffering from other gastrointestinal disorders. Both gluten patch and placebo patch were attached to the skin between the scapulas. The results were read twice: 48 hours and 96 hours after the patch was applied. Patients who showed irritation reactions were withdrawn from this study. The results were analysed by SPSS software, Spearman's test, chi square, and Mann–Whitney tests.
Findings
The value obtained from the gluten patch test after 96 hours are as follows: specification at 95%, sensitivity at 8%, positive prediction value at 67%, and negative prediction value at 43%.
Conclusion
It can be concluded that the gluten patch test is not an efficient test for screening of celiac disease, however, it can be useful for diagnosis of celiac disease if employed and studied with clinical symptoms and serologic and biopsy tests. Furthermore, we should doubt our judgment if the result of gluten patch test for the patient with celiac disease is positive.
PMCID: PMC3446132  PMID: 23056837
Celiac Disease; Food Allergy; Gluten Patch Test
15.  Celiac disease 
Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.
doi:10.1186/1750-1172-1-3
PMCID: PMC1435993  PMID: 16722573
16.  Non-celiac gluten sensitivity - why worry? 
BMC Medicine  2014;12:86.
Wheat, once thought to be a critical ingredient in a healthy diet, has become a major threat, according to public opinion. The term non-celiac gluten sensitivity has been widely adopted to describe a clinical entity characterized by symptoms induced by gluten without the diagnostic criteria found in other gluten-related disorders. However, it has not been shown that gluten per se is involved, and it can be debated if the condition is a disease. Nevertheless, a large number of individuals go gluten-free, avoiding wheat, rye and barley, even without a defined medical cause. In a study in BMC Medicine, Volta and colleagues from Italy report on a large, multicenter attempt to enumerate the prevalence of non-celiac gluten sensitivity in secondary gastroenterology care. They found that approximately 3% of their more than 12,000 patients fulfilled their criteria for non-celiac gluten sensitivity. However, we are still challenged with finding stricter clinical criteria for the condition, developing a usable clinical approach for gluten challenge in these individuals, and understanding the pathogenesis of the condition.
Please see related article http://www.biomedcentral.com/1741-7015/12/85.
doi:10.1186/1741-7015-12-86
PMCID: PMC4031484  PMID: 24885490
Celiac disease; Diagnosis; FODMAP; Gluten; Gluten-free diet; Irritable bowel syndrome; Multicenter study; Non-celiac gluten sensitivity
17.  Clinical benefit of gluten-free diet in screen-detected older celiac disease patients 
BMC Gastroenterology  2011;11:136.
Background
The utility of serologic screening for celiac disease is still debatable. Evidence suggests that the disorder remains undetected even in the older population. It remains obscure whether screening makes good or harm in subjects with long-standing gluten ingestion. We evaluated whether older subjects benefit from active detection and subsequent gluten free dietary treatment of celiac disease.
Methods
Thirty-five biopsy-proven patients aged over 50 years had been detected by serologic mass screening. We examined the disease history, dietary compliance, symptoms, quality of life and bone mineral density at baseline and 1-2 years after the commencement of a gluten-free diet. Symptoms were evaluated by gastrointestinal symptom rating scale and quality of life by psychological general well-being questionnaires. Small bowel biopsy, serology, laboratory parameters assessing malabsorption, and bone mineral density were investigated.
Results
Dietary compliance was good. The patients had initially low mean serum ferritin values indicating subclinical iron deficiency, which was restored by a gluten-free diet. Vitamin B12, vitamin D and erythrocyte folic acid levels increased significantly on diet. Celiac patients had a history of low-energy fractures more often than the background population, and the diet had a beneficial effect on bone mineral density. Alleviation in gastrointestinal symptoms was observed, even though the patients reported no or only subtle symptoms at diagnosis. Quality of life remained unchanged. Of all the cases, two thirds would have been diagnosed even without screening if the family history, fractures or concomitant autoimmune diseases had been taken carefully into account.
Conclusions
Screen-detected patients benefited from a gluten-free diet. We encourage a high index of suspicion and active case-finding in celiac disease as an alternative to mass screening in older patients.
doi:10.1186/1471-230X-11-136
PMCID: PMC3377922  PMID: 22176557
18.  Functional Bowel Disorders in Iranian Population using Rome III Criteria 
Background/Aim:
To study the prevalence and risk factors of functional bowel disorders (FBD) in Iranian community using Rome III criteria.
Materials and Methods:
This study was a cross-sectional household survey conducted from May 2006 to December 2007 in Tehran province, Iran, including 18,180 participants who were selected randomly and interviewed face-to-face by a validated questionnaire based on Rome III criteria.
Results:
In all, 1.1% met the Rome III criteria for irritable bowel syndrome (IBS), 2.4% for functional constipation (FC), and 10.9% of the participants had any type of FBD. Among participants with functional dyspepsia, 83.8% had FBD; the majority cases were unspecified functional bowel disorder (U-FBD). Of the subjects fulfilling the IBS criteria, IBS with constipation (52%) was the most frequent subtype. In the multivariate analysis, women had a higher risk of any FBDs than men, except for functional diarrhea (FD). The prevalence of FBD, FC and FD increased and IBS decreased with increasing age. Marital status was only associated with a decrease in the risk of FBD and FD, respectively. IBS subtypes compared with FC and FD. There was no significant difference between FC and IBS with constipation (IBS-C), except for self-reported constipation; while, IBS with diarrhea (IBS-D) had more symptoms than FD.
Conclusion:
This study revealed a low rate of FBDs among the urban population of Tehran province. The ROME III criteria itself, and the problems with interpretation of the data collection tool may have contributed in underestimating the prevalence of FBD. In addition the reliability of recall over 6 months in Rome III criteria is questionable for our population.
doi:10.4103/1319-3767.65183
PMCID: PMC3003223  PMID: 20616409
Functional bowel disorder; IBS; bloating; constipation; diarrhea; Rome III criteria
19.  What Role Does Wheat Play in the Symptoms of Irritable Bowel Syndrome? 
Gastroenterology & Hepatology  2013;9(2):85-91.
Recently, increasing attention has been paid to the pathologic role of food in irritable bowel syndrome (IBS). Nevertheless, healthcare providers often avoid addressing diet with their patients because of a lack of training, guideline consensus, and high-quality data. Recent literature supports the existence of a subgroup of IBS patients with undiagnosed nonceliac gluten sensitivity (NCGS), a term that is used to describe individuals who experience gastrointestinal and extraintestinal symptoms as a result of immunologic, morphologic, or symptomatic abnormalities that are precipitated by the ingestion of gluten. NCGS represents an important subgroup of patients with IBS who are highly treatable via dietary modification. Gluten may influence gastrointestinal symptoms through immune activation or alteration of intestinal permeability, but the true role of food in functional gastrointestinal symptomatology remains unclear. For example, gluten is just 1 component of the complex milieu of nutrients found in wheat and related grains, and NCGS likely represents only the tip of the iceberg as it pertains to the role of food in IBS.
PMCID: PMC3754775  PMID: 23983652
Celiac disease; food; gluten sensitivity; irritable bowel syndrome; wheat intolerance
20.  Investigation of the effect of military stress on the prevalence of functional bowel disorders 
AIM: To investigate the morbidity of functional bowel disorders (FBD) under military stress conditions in order to lay foundations for the prevention and treatment of this disease.
METHODS: Four hundred and fifty-seven soldiers who were assigned to specified services and 471 soldiers who were assigned to routine services were enrolled using cluster sampling, with the latter as a control group. They were surveyed using the Rome III FBD standard questionnaire. The FBD symptom questionnaire included FBD-related symptoms, severity, duration or attack time, and accompanying symptoms.
RESULTS: The morbidity of the military stress group (14.6%) was significantly higher than in the control group (9.98%) (χ2 = 4.585, P < 0.05). The incidence of smoking, abdominal pain and acid regurgitation (χ2 = 4.761, P < 0.05) as well as the ZUNG anxiety/depression scores (χ2 = 7.982, P < 0.01) were also significantly higher in the military stress group compared with the control group. ZUNG anxiety (χ2 = 11.523, P < 0.01) and depression (χ2 = 5.149, P < 0.05) scores were higher in the FBD group compared with the non-FBD group. The differences in the ZUNG self-rated anxiety and depression scales between the 2 groups were statistically significant (χ2 = 14.482, P < 0.01 and χ2 = 6.176, P < 0.05).
CONCLUSION: The morbidity of FBD was higher under military stress conditions.
doi:10.3748/wjg.v18.i23.3004
PMCID: PMC3380329  PMID: 22736925
Military stress; Functional bowel disorders; Soldier; Self-rating anxiety; Depression scale
21.  Gluten related disorders 
Gluten associated disorders and the question around these associations has recently attracted attentions of many health professionals. This is because of high prevalence of undiagnosed gluten related disorders presenting with a multitude of symptoms and complications inside and outside small bowel. While the environmental factors associated with a complex genetics are leading to destructions of the small intestinal villi resulting in malabsorption syndrome in CD, GS is characterised by negative antibodies and grossly normal histology. The association between celiac disease and other disorders has been clearly established and there have been many reports of numerous intestinal and extra intestinal coexistent disorders with CD. But there is little information available regarding the clinical behavior of gluten sensitivity. In this review we discuss the clinical presentation of non-celiac GS and the prospect of current and the future diagnostic pathway.
PMCID: PMC4017485  PMID: 24834231
Celiac disease; Gluten sensitivity; Differentiation; Histology
22.  Long-Term Consumption of Oats in Adult Celiac Disease Patients 
Nutrients  2013;5(11):4380-4389.
Many celiac disease patients tolerate oats, but limited data are available on its long-term consumption. This was evaluated in the present study, focusing on small-bowel mucosal histology and gastrointestinal symptoms in celiac adults maintaining a strict gluten-free diet with or without oats. Altogether 106 long-term treated celiac adults were enrolled for this cross-sectional follow-up study. Daily consumption of oats and fiber was assessed, and small-bowel mucosal morphology and densities of CD3+, αβ+ and γσ+ intraepithelial lymphocytes determined. Gastrointestinal symptoms were assessed by a validated Gastrointestinal Symptom Rating Scale questionnaire. Seventy (66%) out of the 106 treated celiac disease patients had consumed a median of 20 g of oats (range 1–100 g) per day for up to eight years; all consumed oat products bought from general stores. Daily intake and long-term consumption of oats did not result in small-bowel mucosal villous damage, inflammation, or gastrointestinal symptoms. Oat-consumers had a significantly higher daily intake of fiber than those who did not use oats. Two thirds of celiac disease patients preferred to use oats in their daily diet. Even long-term ingestion of oats had no harmful effects.
doi:10.3390/nu5114380
PMCID: PMC3847736  PMID: 24201240
celiac disease; gluten-free diet; morphology; oats; questionnaire; small-bowel
23.  Gluten Sensitivity Presenting as a Neuropsychiatric Disorder 
There has been increasing recognition in the medical community and the general public of the widespread prevalence of gluten sensitivity. Celiac disease (CD) was initially believed to be the sole source of this phenomenon. Signs and symptoms indicative of nonceliac gluten sensitivity (NCGS), in which classical serum and intestinal findings of CD may be absent, have been frequently reported of late. Clinical manifestations in patients with NCGS are characteristically triggered by gluten and are ameliorated or resolved within days to weeks of commencing a gluten-free diet. Emerging scientific literature contains several reports linking gluten sensitivity states with neuropsychiatric manifestations including autism, schizophrenia, and ataxia. A clinical review of gluten sensitivity is presented alongside a case illustrating the life-changing difference achieved by gluten elimination in a patient with a longstanding history of auditory and visual hallucinations. Physicians in clinical practice should routinely consider sensitivity issues as an etiological determinant of otherwise inexplicable symptoms. Pathophysiologic mechanisms to explain the multisystem symptomatology with gluten sensitivity are considered.
doi:10.1155/2014/293206
PMCID: PMC3944951  PMID: 24693281
24.  Chronic urticaria: A cutaneous manifestation of celiac disease 
Celiac disease, or gluten-sensitive enteropathy, is an immune-mediated disease of the small bowel that results in malabsorption. It classically presents with gastrointestinal symptoms including chronic diarrhea, weight loss, abdominal bloating and anorexia. It is becoming more frequently identified in asymptomatic patients with a diagnosis of deficiencies related to malabsorption of iron, folic acid, vitamin B12 and vitamin D. It is increasingly identified as a cause for early or refractory osteoporosis. Occasionally, celiac disease presents with cutaneous manifestations alone. Dermatitis herpetiformis is a well-recognized cutaneous manifestation of celiac disease. Other cutaneous manifestations include alopecia, angular stomatitis and aphthous ulcerations. Described here is a case of a 24-year-old woman who presented with intermittent urticaria and gastrointestinal complaints. She was found to have celiac disease on small-bowel biopsy. Both her gastrointestinal symptoms and urticaria resolved when she was put on a gluten-free diet, suggesting that her urticaria was a cutaneous manifestation of celiac disease.
PMCID: PMC2659909  PMID: 16609761
Celiac disease; Chronic urticaria
25.  Clinical impact of a gluten-free diet on health-related quality of life in seven fibromyalgia syndrome patients with associated celiac disease 
BMC Gastroenterology  2013;13:157.
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.
doi:10.1186/1471-230X-13-157
PMCID: PMC3835396  PMID: 24209578
Gluten-free diet; Celiac disease; Fibromyalgia syndrome; Irritable bowel syndrome; Health-related quality of life

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