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1.  Clinical Utility of Serologic Testing for Celiac Disease in Ontario 
Executive Summary
Objective of Analysis
The objective of this evidence-based evaluation is to assess the accuracy of serologic tests in the diagnosis of celiac disease in subjects with symptoms consistent with this disease. Furthermore the impact of these tests in the diagnostic pathway of the disease and decision making was also evaluated.
Celiac Disease
Celiac disease is an autoimmune disease that develops in genetically predisposed individuals. The immunological response is triggered by ingestion of gluten, a protein that is present in wheat, rye, and barley. The treatment consists of strict lifelong adherence to a gluten-free diet (GFD).
Patients with celiac disease may present with a myriad of symptoms such as diarrhea, abdominal pain, weight loss, iron deficiency anemia, dermatitis herpetiformis, among others.
Serologic Testing in the Diagnosis Celiac Disease
There are a number of serologic tests used in the diagnosis of celiac disease.
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibodies (DGP)
Serologic tests are automated with the exception of the EMA test, which is more time-consuming and operator-dependent than the other tests. For each serologic test, both immunoglobulin A (IgA) or G (IgG) can be measured, however, IgA measurement is the standard antibody measured in celiac disease.
Diagnosis of Celiac Disease
According to celiac disease guidelines, the diagnosis of celiac disease is established by small bowel biopsy. Serologic tests are used to initially detect and to support the diagnosis of celiac disease. A small bowel biopsy is indicated in individuals with a positive serologic test. In some cases an endoscopy and small bowel biopsy may be required even with a negative serologic test. The diagnosis of celiac disease must be performed on a gluten-containing diet since the small intestine abnormalities and the serologic antibody levels may resolve or improve on a GFD.
Since IgA measurement is the standard for the serologic celiac disease tests, false negatives may occur in IgA-deficient individuals.
Incidence and Prevalence of Celiac Disease
The incidence and prevalence of celiac disease in the general population and in subjects with symptoms consistent with or at higher risk of celiac disease based on systematic reviews published in 2004 and 2009 are summarized below.
Incidence of Celiac Disease in the General Population
Adults or mixed population: 1 to 17/100,000/year
Children: 2 to 51/100,000/year
In one of the studies, a stratified analysis showed that there was a higher incidence of celiac disease in younger children compared to older children, i.e., 51 cases/100,000/year in 0 to 2 year-olds, 33/100,000/year in 2 to 5 year-olds, and 10/100,000/year in children 5 to 15 years old.
Prevalence of Celiac Disease in the General Population
The prevalence of celiac disease reported in population-based studies identified in the 2004 systematic review varied between 0.14% and 1.87% (median: 0.47%, interquartile range: 0.25%, 0.71%). According to the authors of the review, the prevalence did not vary by age group, i.e., adults and children.
Prevalence of Celiac Disease in High Risk Subjects
Type 1 diabetes (adults and children): 1 to 11%
Autoimmune thyroid disease: 2.9 to 3.3%
First degree relatives of patients with celiac disease: 2 to 20%
Prevalence of Celiac Disease in Subjects with Symptoms Consistent with the Disease
The prevalence of celiac disease in subjects with symptoms consistent with the disease varied widely among studies, i.e., 1.5% to 50% in adult studies, and 1.1% to 17% in pediatric studies. Differences in prevalence may be related to the referral pattern as the authors of a systematic review noted that the prevalence tended to be higher in studies whose population originated from tertiary referral centres compared to general practice.
Research Questions
What is the sensitivity and specificity of serologic tests in the diagnosis celiac disease?
What is the clinical validity of serologic tests in the diagnosis of celiac disease? The clinical validity was defined as the ability of the test to change diagnosis.
What is the clinical utility of serologic tests in the diagnosis of celiac disease? The clinical utility was defined as the impact of the test on decision making.
What is the budget impact of serologic tests in the diagnosis of celiac disease?
What is the cost-effectiveness of serologic tests in the diagnosis of celiac disease?
Methods
Literature Search
A literature search was performed on November 13th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st 2003 and November 13th 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Studies that evaluated diagnostic accuracy, i.e., both sensitivity and specificity of serology tests in the diagnosis of celiac disease.
Study population consisted of untreated patients with symptoms consistent with celiac disease.
Studies in which both serologic celiac disease tests and small bowel biopsy (gold standard) were used in all subjects.
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, and retrospective cohort studies.
At least 20 subjects included in the celiac disease group.
English language.
Human studies.
Studies published from 2000 on.
Clearly defined cut-off value for the serology test. If more than one test was evaluated, only those tests for which a cut-off was provided were included.
Description of small bowel biopsy procedure clearly outlined (location, number of biopsies per patient), unless if specified that celiac disease diagnosis guidelines were followed.
Patients in the treatment group had untreated CD.
Studies on screening of the general asymptomatic population.
Studies that evaluated rapid diagnostic kits for use either at home or in physician’s offices.
Studies that evaluated diagnostic modalities other than serologic tests such as capsule endoscopy, push enteroscopy, or genetic testing.
Cut-off for serologic tests defined based on controls included in the study.
Study population defined based on positive serology or subjects pre-screened by serology tests.
Celiac disease status known before study enrolment.
Sensitivity or specificity estimates based on repeated testing for the same subject.
Non-peer-reviewed literature such as editorials and letters to the editor.
Population
The population consisted of adults and children with untreated, undiagnosed celiac disease with symptoms consistent with the disease.
Serologic Celiac Disease Tests Evaluated
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibody (DGP)
Combinations of some of the serologic tests listed above were evaluated in some studies
Both IgA and IgG antibodies were evaluated for the serologic tests listed above.
Outcomes of Interest
Sensitivity
Specificity
Positive and negative likelihood ratios
Diagnostic odds ratio (OR)
Area under the sROC curve (AUC)
Small bowel biopsy was used as the gold standard in order to estimate the sensitivity and specificity of each serologic test.
Statistical Analysis
Pooled estimates of sensitivity, specificity and diagnostic odds ratios (DORs) for the different serologic tests were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance for differences in sensitivity and specificity between serologic tests was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. The bivariate regression analyses were performed using SAS version 9.2 (SAS Institute Inc.; Cary, NC, USA). Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced using Review Manager 5.0.22 (The Nordiac Cochrane Centre, The Cochrane Collaboration, 2008). The area under the sROC curve (AUC) was estimated by bivariate mixed-efects binary regression modeling framework. Model specification, estimation and prediction are carried out with xtmelogit in Stata release 10 (Statacorp, 2007). Statistical tests for the differences in AUC estimates could not be carried out.
The study results were stratified according to patient or disease characteristics such as age, severity of Marsh grade abnormalities, among others, if reported in the studies. The literature indicates that the diagnostic accuracy of serologic tests for celiac disease may be affected in patients with chronic liver disease, therefore, the studies identified through the systematic literature review that evaluated the diagnostic accuracy of serologic tests for celiac disease in patients with chronic liver disease were summarized. The effect of the GFD in patiens diagnosed with celiac disease was also summarized if reported in the studies eligible for the analysis.
Summary of Findings
Published Systematic Reviews
Five systematic reviews of studies that evaluated the diagnostic accuracy of serologic celiac disease tests were identified through our literature search. Seventeen individual studies identified in adults and children were eligible for this evaluation.
In general, the studies included evaluated the sensitivity and specificity of at least one serologic test in subjects with symptoms consistent with celiac disease. The gold standard used to confirm the celiac disease diagnosis was small bowel biopsy. Serologic tests evaluated included tTG, EMA, AGA, and DGP, using either IgA or IgG antibodies. Indirect immunoflurorescence was used for the EMA serologic tests whereas enzyme-linked immunosorbent assay (ELISA) was used for the other serologic tests.
Common symptoms described in the studies were chronic diarrhea, abdominal pain, bloating, unexplained weight loss, unexplained anemia, and dermatitis herpetiformis.
The main conclusions of the published systematic reviews are summarized below.
IgA tTG and/or IgA EMA have a high accuracy (pooled sensitivity: 90% to 98%, pooled specificity: 95% to 99% depending on the pooled analysis).
Most reviews found that AGA (IgA or IgG) are not as accurate as IgA tTG and/or EMA tests.
A 2009 systematic review concluded that DGP (IgA or IgG) seems to have a similar accuracy compared to tTG, however, since only 2 studies identified evaluated its accuracy, the authors believe that additional data is required to draw firm conclusions.
Two systematic reviews also concluded that combining two serologic celiac disease tests has little contribution to the accuracy of the diagnosis.
MAS Analysis
Sensitivity
The pooled analysis performed by MAS showed that IgA tTG has a sensitivity of 92.1% [95% confidence interval (CI) 88.0, 96.3], compared to 89.2% (83.3, 95.1, p=0.12) for IgA DGP, 85.1% (79.5, 94.4, p=0.07) for IgA EMA, and 74.9% (63.6, 86.2, p=0.0003) for IgA AGA. Among the IgG-based tests, the results suggest that IgG DGP has a sensitivity of 88.4% (95% CI: 82.1, 94.6), 44.7% (30.3, 59.2) for tTG, and 69.1% (56.0, 82.2) for AGA. The difference was significant when IgG DGP was compared to IgG tTG but not IgG AGA. Combining serologic celiac disease tests yielded a slightly higher sensitivity compared to individual IgA-based serologic tests.
IgA deficiency
The prevalence of total or severe IgA deficiency was low in the studies identified varying between 0 and 1.7% as reported in 3 studies in which IgA deficiency was not used as a referral indication for celiac disease serologic testing. The results of IgG-based serologic tests were positive in all patients with IgA deficiency in which celiac disease was confirmed by small bowel biopsy as reported in four studies.
Specificity
The MAS pooled analysis indicates a high specificity across the different serologic tests including the combination strategy, pooled estimates ranged from 90.1% to 98.7% depending on the test.
Likelihood Ratios
According to the likelihood ratio estimates, both IgA tTG and serologic test combinationa were considered very useful tests (positive likelihood ratio above ten and the negative likelihood ratio below 0.1).
Moderately useful tests included IgA EMA, IgA DGP, and IgG DGP (positive likelihood ratio between five and ten and the negative likelihood ratio between 0.1 and 0.2).
Somewhat useful tests: IgA AGA, IgG AGA, generating small but sometimes important changes from pre- to post-test probability (positive LR between 2 and 5 and negative LR between 0.2 and 0.5)
Not Useful: IgG tTG, altering pre- to post-test probability to a small and rarely important degree (positive LR between 1 and 2 and negative LR between 0.5 and 1).
Diagnostic Odds Ratios (DOR)
Among the individual serologic tests, IgA tTG had the highest DOR, 136.5 (95% CI: 51.9, 221.2). The statistical significance of the difference in DORs among tests was not calculated, however, considering the wide confidence intervals obtained, the differences may not be statistically significant.
Area Under the sROC Curve (AUC)
The sROC AUCs obtained ranged between 0.93 and 0.99 for most IgA-based tests with the exception of IgA AGA, with an AUC of 0.89.
Sensitivity and Specificity of Serologic Tests According to Age Groups
Serologic test accuracy did not seem to vary according to age (adults or children).
Sensitivity and Specificity of Serologic Tests According to Marsh Criteria
Four studies observed a trend towards a higher sensitivity of serologic celiac disease tests when Marsh 3c grade abnormalities were found in the small bowel biopsy compared to Marsh 3a or 3b (statistical significance not reported). The sensitivity of serologic tests was much lower when Marsh 1 grade abnormalities were found in small bowel biopsy compared to Marsh 3 grade abnormalities. The statistical significance of these findings were not reported in the studies.
Diagnostic Accuracy of Serologic Celiac Disease Tests in Subjects with Chronic Liver Disease
A total of 14 observational studies that evaluated the specificity of serologic celiac disease tests in subjects with chronic liver disease were identified. All studies evaluated the frequency of false positive results (1-specificity) of IgA tTG, however, IgA tTG test kits using different substrates were used, i.e., human recombinant, human, and guinea-pig substrates. The gold standard, small bowel biopsy, was used to confirm the result of the serologic tests in only 5 studies. The studies do not seem to have been designed or powered to compare the diagnostic accuracy among different serologic celiac disease tests.
The results of the studies identified in the systematic literature review suggest that there is a trend towards a lower frequency of false positive results if the IgA tTG test using human recombinant substrate is used compared to the guinea pig substrate in subjects with chronic liver disease. However, the statistical significance of the difference was not reported in the studies. When IgA tTG with human recombinant substrate was used, the number of false positives seems to be similar to what was estimated in the MAS pooled analysis for IgA-based serologic tests in a general population of patients. These results should be interpreted with caution since most studies did not use the gold standard, small bowel biopsy, to confirm or exclude the diagnosis of celiac disease, and since the studies were not designed to compare the diagnostic accuracy among different serologic tests. The sensitivity of the different serologic tests in patients with chronic liver disease was not evaluated in the studies identified.
Effects of a Gluten-Free Diet (GFD) in Patients Diagnosed with Celiac Disease
Six studies identified evaluated the effects of GFD on clinical, histological, or serologic improvement in patients diagnosed with celiac disease. Improvement was observed in 51% to 95% of the patients included in the studies.
Grading of Evidence
Overall, the quality of the evidence ranged from moderate to very low depending on the serologic celiac disease test. Reasons to downgrade the quality of the evidence included the use of a surrogate endpoint (diagnostic accuracy) since none of the studies evaluated clinical outcomes, inconsistencies among study results, imprecise estimates, and sparse data. The quality of the evidence was considered moderate for IgA tTg and IgA EMA, low for IgA DGP, and serologic test combinations, and very low for IgA AGA.
Clinical Validity and Clinical Utility of Serologic Testing in the Diagnosis of Celiac Disease
The clinical validity of serologic tests in the diagnosis of celiac disease was considered high in subjects with symptoms consistent with this disease due to
High accuracy of some serologic tests.
Serologic tests detect possible celiac disease cases and avoid unnecessary small bowel biopsy if the test result is negative, unless an endoscopy/ small bowel biopsy is necessary due to the clinical presentation.
Serologic tests support the results of small bowel biopsy.
The clinical utility of serologic tests for the diagnosis of celiac disease, as defined by its impact in decision making was also considered high in subjects with symptoms consistent with this disease given the considerations listed above and since celiac disease diagnosis leads to treatment with a gluten-free diet.
Economic Analysis
A decision analysis was constructed to compare costs and outcomes between the tests based on the sensitivity, specificity and prevalence summary estimates from the MAS Evidence-Based Analysis (EBA). A budget impact was then calculated by multiplying the expected costs and volumes in Ontario. The outcome of the analysis was expected costs and false negatives (FN). Costs were reported in 2010 CAD$. All analyses were performed using TreeAge Pro Suite 2009.
Four strategies made up the efficiency frontier; IgG tTG, IgA tTG, EMA and small bowel biopsy. All other strategies were dominated. IgG tTG was the least costly and least effective strategy ($178.95, FN avoided=0). Small bowel biopsy was the most costly and most effective strategy ($396.60, FN avoided =0.1553). The cost per FN avoided were $293, $369, $1,401 for EMA, IgATTG and small bowel biopsy respectively. One-way sensitivity analyses did not change the ranking of strategies.
All testing strategies with small bowel biopsy are cheaper than biopsy alone however they also result in more FNs. The most cost-effective strategy will depend on the decision makers’ willingness to pay. Findings suggest that IgA tTG was the most cost-effective and feasible strategy based on its Incremental Cost-Effectiveness Ratio (ICER) and convenience to conduct the test. The potential impact of IgA tTG test in the province of Ontario would be $10.4M, $11.0M and $11.7M respectively in the following three years based on past volumes and trends in the province and basecase expected costs.
The panel of tests is the commonly used strategy in the province of Ontario therefore the impact to the system would be $13.6M, $14.5M and $15.3M respectively in the next three years based on past volumes and trends in the province and basecase expected costs.
Conclusions
The clinical validity and clinical utility of serologic tests for celiac disease was considered high in subjects with symptoms consistent with this disease as they aid in the diagnosis of celiac disease and some tests present a high accuracy.
The study findings suggest that IgA tTG is the most accurate and the most cost-effective test.
AGA test (IgA) has a lower accuracy compared to other IgA-based tests
Serologic test combinations appear to be more costly with little gain in accuracy. In addition there may be problems with generalizability of the results of the studies included in this review if different test combinations are used in clinical practice.
IgA deficiency seems to be uncommon in patients diagnosed with celiac disease.
The generalizability of study results is contingent on performing both the serologic test and small bowel biopsy in subjects on a gluten-containing diet as was the case in the studies identified, since the avoidance of gluten may affect test results.
PMCID: PMC3377499  PMID: 23074399
2.  In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes 
PLoS Medicine  2006;3(9):e358.
Background
Celiac disease is a small intestine inflammatory disorder with multiple organ involvement, sustained by an inappropriate immune response to dietary gluten. Anti-transglutaminase antibodies are a typical serological marker in patients with active disease, and may disappear during a gluten-free diet treatment. Involvement of infectious agents and innate immunity has been suggested but never proven. Molecular mimicry is one of the mechanisms that links infection and autoimmunity.
Methods and Findings
In our attempt to clarify the pathogenesis of celiac disease, we screened a random peptide library with pooled sera of patients affected by active disease after a pre-screening with the sera of the same patients on a gluten-free diet. We identified a peptide recognized by serum immunoglobulins of patients with active disease, but not by those of patients on a gluten-free diet. This peptide shares homology with the rotavirus major neutralizing protein VP-7 and with the self-antigens tissue transglutaminase, human heat shock protein 60, desmoglein 1, and Toll-like receptor 4. We show that antibodies against the peptide affinity-purified from the sera of patients with active disease recognize the viral product and self-antigens in ELISA and Western blot. These antibodies were able to induce increased epithelial cell permeability evaluated by transepithelial flux of [3H] mannitol in the T84 human intestinal epithelial cell line. Finally, the purified antibodies induced monocyte activation upon binding Toll-like receptor 4, evaluated both by surface expression of activation markers and by production of pro-inflammatory cytokines.
Conclusions
Our findings show that in active celiac disease, a subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of the disease, through a mechanism of molecular mimicry. Moreover, such antibodies recognize self-antigens and are functionally active, able to increase intestinal permeability and induce monocyte activation. We therefore provide evidence for the involvement of innate immunity in the pathogenesis of celiac disease through a previously unknown mechanism of engagement of Toll-like receptor 4.
A subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of celiac disease through a mechanism of molecular mimicry.
Editors' Summary
Background.
Celiac disease is an autoimmune, digestive disorder in which the small intestine (the part of the gut that absorbs nutrients from food) is damaged. In autoimmune diseases, the immune system, which normally provides protection against foreign invaders, attacks a person's own tissues. In celiac disease, this attack is triggered by eating food containing gluten, a mixture of proteins found in wheat, barley, and rye. To avoid malnutrition, people with celiac disease—about one in 100 people of north European descent—must follow a strict, lifelong gluten-free diet, one that avoids baked products, wheat, pasta, and many other foods. If they fail to do this, their immune system may attack not only their gut but also their brain, skin, joints, and other tissues, in part through the production of antibodies (autoantibodies) that recognize a protein (self-antigen) called tissue transglutaminase. Celiac disease is diagnosed also by looking for these autoantibodies in patients' blood when they are on a gluten-containing diet; they rapidly disappear when a gluten-free diet is adopted.
Why Was This Study Done?
A gluten-free diet keeps celiac disease in check but does not cure it and is very difficult to follow. Even the minute amounts of gluten found in medicines, for example, can trigger the production of autoantibodies and active disease. But developing a cure is impossible without a better understanding of how celiac disease develops. Why, for example, do celiac disease patients make anti-transglutaminase antibodies? Were they made initially to ward off an infectious agent but unfortunately also recognized transglutaminase? In this study, the researchers asked whether “molecular mimicry”—cross-reactivity between self-molecules and foreign molecules on bacteria or viruses (pathogens)—might initiate celiac disease. They also asked whether innate immunity (the part of the immune system that responds quickly to general features on pathogens) as well as adaptive immunity (the production of antibodies and immune cells that recognize specific features on pathogens) is involved in the development of celiac disease.
What Did the Researchers Do and Find?
The researchers purified antibodies from blood provided by patients with celiac disease when they were eating food containing gluten and when they were on a gluten-free diet. They used these to identify celiac peptide, a synthetic protein fragment that was recognized only by the antibodies made by patients with active disease. By searching a database of pathogen proteins, the researchers discovered that rotavirus protein VP-7 contains a very similar peptide; a search of a database of human proteins indicated that celiac peptide also resembles peptides found in tissue transglutaminase, Toll-like receptor 4 (TLR4; a protein involved in the innate immune response), and several other self-antigens. Patient antibodies purified through their ability to bind to celiac peptide also bound to VP-7 and to these self-antigens, and only patients with active disease made these antibodies. The researchers also investigated whether these anti-celiac peptide antibodies might affect the gut or the innate immune system. The antibodies increased the permeability of a layer of gut cells growing in a laboratory dish by interacting with the self-antigen desmoglein 1. This protein helps to make impermeable seals between the cells that line the gut so that food antigens in the gut cannot seep out into the tissues where the immune system might detect them. In addition, by binding to TLR4, the anti-celiac peptide antibodies activated monocytes—cells that function in both the innate and adaptive immune response.
What Do These Findings Mean?
The finding that some anti-transglutaminase antibodies recognize the viral protein VP-7 could mean that rotavirus infection, which causes gastroenteritis, helps to initiate celiac disease in susceptible individuals through molecular mimicry. Furthermore, the identification of other self-antigens that contain peptides recognized by the antibodies made during active disease starts to explain why damage occurs outside the gut in people with celiac disease. The ability of these antibodies to recognize all these peptides could be coincidental, but the observation that the antibodies have relevant functional effects—the ability to increase intestinal permeability and to activate monocytes—makes this less likely. More research is needed to reveal exactly how infections and the innate immune response affect the development of celiac disease, but every piece of new information brings the possibility of a cure a little closer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030358.
US National Institute of Diabetes and Digestive and Kidney Diseases, information for patients on celiac disease
MedlinePlus encyclopedia entries on celiac disease and on autoimmunity
Wikipedia pages on celiac disease and on autoimmunity (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030358
PMCID: PMC1569884  PMID: 16984219
3.  Clinical Utility of Serologic Testing for Celiac Disease in Asymptomatic Patients 
Executive Summary
Objective
The objective of this evidence-based analysis was to evaluate the clinical utility of serologic testing for celiac disease in asymptomatic individuals presenting with one of the non-gastrointestinal conditions evaluated in this report. The clinical utility was based on the effects of a gluten-free diet (GFD) on outcomes specific to each of these conditions. The prevalence of celiac disease in asymptomatic individuals and one of these non-gastrointestinal conditions was also evaluated.
Clinical Need and Target Population
Celiac Disease
Celiac disease is an autoimmune disease characterized by a chronic inflammatory state of the proximal small bowel mucosa accompanied by structural and functional changes.
Technology Under Evaluation
Serologic Tests for Celiac Disease
There are a number of serologic tests for celiac disease available. Serologic tests are automated with the exception of the anti-endomysial antibody test, which is more time-consuming and operator-dependent than the other tests.
Research Questions
What is the prevalence of asymptomatic celiac disease in patients presenting with one of the non-gastrointestinal conditions evaluated?
What is the effect of the gluten-free diet on condition-specific outcomes in patients with asymptomatic celiac disease presenting with one of the non-gastrointestinal conditions evaluated?
What is the clinical utility of serologic testing for celiac disease in asymptomatic patients presenting with one of the non-gastrointestinal conditions evaluated? The clinical utility was defined as the impact of the GFD on disease specific outcomes.
What is the risk of all-cause mortality and lymphoma in individuals with asymptomatic celiac disease?
What is the budget impact of serologic testing for celiac disease in asymptomatic subjects presenting with one of the non-gastrointestinal conditions evaluated?
Research Methods
Study Population
The study population consisted of individuals with newly diagnosed celiac disease without any symptoms consistent with the disease presenting with one of the non-gastrointestinal conditions evaluated. When evaluating the risk of lymphoma and all-cause mortality, the study population consisted of asymptomatic individuals with a positive celiac disease serologic test and/or small bowel biopsy.
Literature Search
Search Strategy
Literature searches were performed for each disease/condition evaluated between December 2010 and March 2011 using OVID MEDLINE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). No restrictions for start date of search were used.
Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Studies, systematic reviews, and meta-analyses that assessed the effects of a GFD in patients with newly diagnosed asymptomatic celiac disease presenting with one of the non-gastrointestinal conditions evaluated. If symptoms were not reported in the study but subjects were identified through screening for celiac disease the study was included.
Studies, systematic reviews, and meta-analyses that assessed the prevalence of newly diagnosed asymptomatic celiac disease in patients with one of the non-gastrointestinal conditions evaluated. If symptoms were not reported in the study but subjects were identified through screening for celiac disease the study was included.
Studies, systematic reviews, and meta-analyses that evaluated the risk of all-cause mortality or lymphoma in individuals with asymptomatic celiac disease.
Sample size ≥ 10.
Publications in English.
Exclusion Criteria
Studies that retrospectively assessed the prevalence of asymptomatic celiac disease.
Studies that reported the prevalence of one of the non-gastrointestinal conditions evaluated in subjects already diagnosed with celiac disease.
Studies in individuals with one of the non-gastrointestinal conditions evaluated if the condition could be explained by other causes.
Studies in subjects with celiac disease and symptoms consistent with the disease. If the study included individuals with and without symptoms consistent with celiac disease and their results were analysed separately, the results in individuals without symptoms were included in the analysis.
Studies in which individuals did not report any symptoms consistent with celiac disease at study start but that either retrospectively reported the presence of such symptoms after following a GFD, or that previously presented with symptoms consistent with celiac disease.
Study results published in letters to the editor or comments about other studies.
Studies with a sample size ≥ 10, however, in which less than 10 patients were included in the analysis.
Outcomes of Interest
The effects of a GFD on disease-specific outcomes for each condition evaluated in patients with asymptomatic celiac disease was assessed. The prevalence of asymptomatic celiac disease in patients presenting with one of the conditions evaluated was also assessed.
Results of Evidence-Based Analysis
Three eligible observational studies evaluated the effects of GFD on growth parameters in subjects with asymptomatic celiac disease and idiopathic short stature. Four eligible observational studies evaluated the effects of GFD on metabolic control in subjects with asymptomatic celiac disease and type 1 diabetes. Five eligible observational studies evaluated the risk of all-cause mortality and five eligible observational studies evaluated the risk of lymphoma in subjects with asymptomatic celiac disease. No eligible studies on the effects of the GFD for the other conditions evaluated were identified. Twenty-three eligible studies measured the prevalence of asymptomatic celiac disease in subjects presenting with one of the conditions evaluated.
Prevalence of Celiac Disease in Asymptomatic Patients
The prevalence of celiac disease in asymptomatic patients presenting with one of the conditions evaluated was analysed. Most studies also included a control group that generally consisted of individuals randomly selected from the general population.
Although there was a trend to a higher prevalence of asymptomatic celiac disease in individuals with the conditions evaluated compared to the controls, it only reached statistical significance in type 1 diabetes. No eligible prevalence studies were identified in patients with amenorrhea, delayed puberty, alopecia, and depression.
The Effects of a Gluten-Free Diet on Disease-Specific Outcomes in Patients with Asymptomatic Celiac Disease
The effects of GFD on metabolic control in patients with asymptomatic celiac disease and Type 1 Diabetes
The effects of a GFD on metabolic control (HbA1c, number of hypoglycemic episodes, and changes in insulin dosage) in subjects with asymptomatic celiac disease and type 1 diabetes were evaluated.
One prospective case-control study reported an increase in HbA1c levels in cases with type 1 diabetes and asymptomatic celiac disease after the introduction of a GFD, however, the clinical significance of this change is unclear.
Only one eligible retrospective case-control study evaluated the effects of a GFD on hypoglycemia episodes and since there were inadequate details in the study about both the ascertainment and severity of hypoglycemia episodes in both cases and controls, it is not possible to draw conclusions regarding the effects of a GFD on hypoglycemia episodes based on this study.
One prospective case-control study did not show a statistically significant change in insulin dosage between cases with type 1 diabetes and asymptomatic celiac disease and controls with type 1 diabetes either before or after the introduction of a GFD.
No eligible studies that evaluated the effects of a GFD on the long-term outcomes of type 1 diabetes such as cardiovascular or renal events in patients with asymptomatic celiac disease were identified.
The effects of a Gluten-Free Diet in Patients with Idiopathic Short Stature and Asymptomatic Celiac Disease
A total of 3 eligible studies were identified. All studies consisted of case series that compared growth parameters in subjects with asymptomatic celiac disease and idiopathic short stature before and after the celiac disease was diagnosed and the GFD was instituted.
Most subjects included in the studies demonstrated an improvement in growth parameters. Compliance with the GFD was not reported in the studies. The results of the studies suggest an increase in growth velocity in pediatric patients with asymptomatic celiac disease and idiopathic short stature once a GFD is introduced.
Risk of lymphoma in patients with asymptomatic celiac disease
One retrospective cohort study evaluated the risk of lymphoma in patients with asymptomatic celiac disease. The authors concluded that the number of events identified was low during the long follow-up period and that the risk of overall malignancies was not increased among patients with asymptomatic celiac disease.
Risk of Asymptomatic Celiac Disease in Patients with Lymphoma
Four case-control studies, one of which retrospective, evaluated the risk of asymptomatic celiac disease in patients newly diagnosed with lymphoma. One retrospective cohort study did not show an increase in the risk of lymphoma among subjects with asymptomatic celiac disease. Three prospective case-control studies did not find a statistically significant risk of asymptomatic celiac disease in patients with newly diagnosed lymphoma.
Risk of All-Cause Mortality in Patients with Asymptomatic Celiac Disease
A total of 5 studies that evaluated the risk of all-cause mortality in asymptomatic patients with celiac disease were identified. There were 5 cohort studies, 2 prospective and 3 retrospective. The two prospective studies did not show an increased risk of all-cause mortality in subjects with asymptomatic celiac disease.
Grading of Evidence
The quality of the evidence for each serologic tests evaluated based on the GRADE Working Group criteria. Overall, the quality of the evidence ranged from low to very low depending on the outcome evaluated.
The Clinical Utility of Serologic Testing for Celiac Disease in Asymptomatic Subjects
Eligible studies that evaluated the effects of a GFD on disease-specific outcomes were only identified for two of the conditions evaluated, type 1 diabetes and idiopathic short stature.
The clinical utility of serologic testing for celiac disease in patients with type 1 diabetes without symptoms consistent with celiac disease was not demonstrated since the studies identified did not provide evidence of the impact of the GFD on either metabolic control or long-term outcomes in these patients.
The clinical utility of serologic testing for celiac disease in patients with idiopathic short stature without symptoms consistent with celiac disease was demonstrated since the studies identified showed an acceleration in growth once the diagnosis of celiac disease was made and a GFD was introduced.
The Budget Impact of Serologic Testing for Celiac Disease in Asymptomatic Patients
The budget impact of serologic testing for celiac disease in asymptomatic patients was calculated for the conditions for which clinical utility for serologic testing was demonstrated. The budget impact in patients with idiopathic short stature without symptoms consistent with celiac disease was estimated as C$552,000 as calculated by multiplying the number of individuals in Ontario with idiopathic short stature that may be eligible for the test by the cost of the serologic test for celiac disease.
Conclusions
Based on a review of the literature, there is an increased risk of asymptomatic celiac disease in patients with type 1 diabetes.
Based on low quality evidence, in patients with idiopathic short stature and asymptomatic celiac disease there is an acceleration in growth once a gluten-free diet is introduced.
With the exception of idiopathic short stature, there was no published evidence of clinical utility of celiac disease testing in asymptomatic patients with respect to a gluten-free diet intervention in the other conditions evaluated.
Based on low to very low quality evidence, asymptomatic celiac disease does not confer an increased risk of lymphoma or mortality.
Similarly, in patients with lymphoma there is no increased risk of asymptomatic celiac disease.
PMCID: PMC3377551  PMID: 23074415
4.  Design of a peptide for immunodetection of IgA antigliadin antibody for the purpose of screening of celiac disease 
Bioinformation  2012;8(2):87-91.
Celiac disease (CD) is gluten induced enteropathy which requires jejunal biopsy for diagnosis. To select the patients for endoscopoic procedure some serologic tests are popular in clinical practice for screening of CD. Although gliadin is one of the key immuno activator of the disease; serological screening by immuno-detection of gliadin is not recommended. In this context we have designed a peptide using tools of computational biology keeping molecular pathogenesis of the disease into consideration such that antigliadin antibody detection based sensitive and specific cost effective tool for screening of celiac disease can be developed. The designed peptide QPFPEP interacts in a stable manner with dimeric immunoglobin A1 molecule and its parent peptide QPFPQP are sequentially present in maximum number of gliadin epitopes. This hexapeptide is predicted to interact with dimeric IgA1, which increases in the biofluids of the CD patients.
Abbreviations
CD - Celiac disease, TT - Tissue transglutamase, IgA - Immunoglobulin A, AGA - antigliadin antibody, Immunoglobulin G - IgG.
PMCID: PMC3282262  PMID: 22359441
Celiac disease; gliadin; peptides; immunoglobulins; autoimmunity
5.  442 Coincidence of Celiac Disease and Gluten Allergy 
Background
The type I or IV of hypersensitivity reactions according to Gell and Coombs classification may be responsible for clinical symptoms observed after ingestion of gluten - containing products. The mechanisms of these reactions are either IgE-dependent or IgE-independent. Celiac disease based on IgE-independent mechanism is classified as gluten hypersensitivity. Clinical manifestation of celiac disease and gluten allergy is often similar. Correct diagnosis of this disease is particularly important due to the different long-term therapeutic procedures. We would like to asses of the incidence of celiac disease in children with gluten allergy.
Methods
The study involved 50 children with abdominal pain, chronic diarrhea, recurrent respiratory and ears inflammation and skin lesions - patients of the Immunological and Gastroenterology Outpatient Clinic of Institute of Mother and Child. The allergy to gluten was confirmed on the basis of positive peripheral blood lymphocytes blast transformation test and detection of allergen-specific IgE antibodies to gluten (f79). In all children plasma concentration of immunoglobulin classes A, G M and IgA or IgG antibodies against tissue transglutaminase (tTGA) were measured.
Results
In children on the study group the type IV of hypersensitivity reaction to gluten was diagnosed. In 3 children specific IgE antibodies to gluten was also confirmed (f79 - I type hypersensitivity). Anti-tissue transglutaminase antibodies both IgA and IgG were detected in 2 children in whom the concentration of IgA and IgG in serum remained within normal range for age. In these children celiac disease was confirmed by jejunal biopsy.
Conclusions
The predominant frequency of type IV of hypersensitivity reactions in children in response to the gluten antigen should be taken into account in diagnosis of food allergy.
In children diagnosed with gluten allergy the test for celiac disease should be performed.
doi:10.1097/01.WOX.0000412205.98939.37
PMCID: PMC3512829
6.  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
7.  AMERICAN COLLEGE OF GASTROENTEROLOGY CLINICAL GUIDELINE: DIAGNOSIS AND MANAGEMENT OF CELIAC DISEASE 
This guideline presents recommendations for the diagnosis and management of patients with celiac disease. Celiac disease is an immune-based reaction to dietary gluten (storage protein for wheat, barley and rye) that primarily affects the small intestine in those with a genetic predisposition and resolves with exclusion of gluten from the diet. There has been a substantial increase in the prevalence of celiac disease over the last 50 years and an increase in the rate of diagnosis in the last 10 years. Celiac disease can present with many symptoms, including typical gastrointestinal symptoms (e.g. diarrhea, steatorrhea, weight loss, bloating, flatulence, abdominal pain) and also non-gastrointestinal abnormalities (e.g. abnormal liver function tests, iron deficiency anemia, bone disease, skin disorders, and many other protean manifestations). Indeed, many individuals with celiac disease may have no symptoms at all. Celiac disease is usually detected by serologic testing of celiac-specific antibodies. The diagnosis is confirmed by duodenal mucosal biopsies. Both serology and biopsy should be performed on a gluten-containing diet. The treatment for celiac disease is primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up. Non-responsive celiac disease occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms should lead to a review of the patient’s original diagnosis to exclude alternative diagnoses, a review of the GFD to ensure there is no obvious gluten contamination, and serologic testing to confirm adherence with the GFD. In addition, evaluation for disorders associated with celiac disease that could cause persistent symptoms, such as microscopic colitis, pancreatic exocrine dysfunction, and complications of celiac disease, such as enteropathy-associated lymphoma or refractory celiac disease, should be entertained. Newer therapeutic modalities are being studied in clinical trials, but are not yet approved for use in practice. Given the incomplete response of many patients to a GFD free diet as well as the difficulty of adherence to the GFD over the long term, development of new effective therapies for symptom control and reversal of inflammation and organ damage are needed. The prevalence of celiac disease is increasing worldwide and many patients with celiac disease remain undiagnosed, highlighting the need for improved strategies in the future for the optimal detection of patients.
doi:10.1038/ajg.2013.79
PMCID: PMC3706994  PMID: 23609613
8.  Open Conformation Tissue Transglutaminase Testing for Celiac Dietary Assessment 
Digestive and Liver Disease  2012;44(5):375-378.
Objectives
Anti tissue-transglutaminase antibody is the mainstay of celiac disease serologic testing. While it has high sensitivity in patients on an unrestricted diet, sensitivity is poor for evaluation of gluten free diet adherence.
Aim
To assess the utility of a novel assay measuring Immunoglobulin-A antibodies to catalytically active open conformation tissue-transglutaminase in assessment of ongoing gluten exposure in celiac disease patients on an alleged gluten free diet.
Methods
Through prospective assessment, 147 patients with celiac disease were divided into good and poor adherence. Open and closed (conventional) tissue-transglutaminase titers were measured using standard ELISA. 50 patients with inflammatory bowel disease served as disease controls.
Results
Overall 128 patients had been on gluten free diet for more than six months and 19 were found to be poorly adherent on dietary review. Within this group 13 (68.4%) and 10 (52.6%) patients respectively were positive for the open conformation and conventional assay (p = 0.51). Two and one control patients tested positive for closed and open assays respectively.
Conclusions
Compared to native assays open conformation tissue-transglutaminase may have higher sensitivity in the poor GFD adherence group and higher specificity in the control population. Larger population studies are warranted to assess whether the open conformation tissue-transglutaminase assay may be superior to the conventional assay.
doi:10.1016/j.dld.2011.12.008
PMCID: PMC3384702  PMID: 22261352
9.  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
10.  Pearls and pitfalls in the diagnosis of adult celiac disease 
In adults with diarrhea or suspected malabsorption, a diagnosis of celiac disease requires that two criteria be fulfilled: first, a demonstration of typical pathological changes of untreated disease in biopsies from the proximal small bowel; and second, evidence should exist that clinical (and/or pathological) changes are gluten-dependent, most often as an unequivocal response to a gluten-free diet. Pathological abnormalities of celiac disease may include severe (‘flat’) or variably severe (mild or moderate) small bowel mucosal architectural abnormalities that are associated with both epithelial cell and lymphoid cell changes, including intraepithelial lymphocytosis. Architectural changes tend to be most severe in the duodenum and proximal jejunum and less severe, or absent, in the ileum. These findings, while characteristic of celiac disease, are not specific because several other conditions can produce similar changes. Some serological assays (eg, tissue transglutaminase antibody assays) are very useful screening tools in clinical practice because of their high specificity and sensitivity, but these do not provide a definitive diagnosis. The most critical step in the diagnosis of celiac disease is the demonstration of its gluten-dependent nature. The clinical response to gluten restriction in celiac disease is usually reflected in the resolution of diarrhea and weight gain. Normalization of biopsy changes can be first shown in the most distal intestinal sites of involvement, and later, sometimes only after prolonged periods (months to years) in the duodenum. Rarely, recurrent (or refractory) celiac disease may occur after an initial gluten-free diet response. Finally, some with ‘sprue-like intestinal disease’ cannot be classified because a diet response fails to occur. This may be a heterogeneous group, although some are eventually found to have a malignant lymphoma.
PMCID: PMC2662202  PMID: 18354756
Celiac disease; Celiac sprue; Gluten-free diet; Gluten-sensitive enteropathy; Small bowel biopsy; Tissue transglutaminase
11.  Detection of Celiac Disease and Lymphocytic Enteropathy by Parallel Serology and Histopathology in a Population-Based Study 
Gastroenterology  2010;139(1):112-119.
Background & Aims
Although serological analysis is used in diagnosis of celiac disease, histopathology is considered most reliable. We performed a prospective study to determine the clinical, pathological and serological spectrum of celiac disease in a general population (Kalixanda study).
Methods
A random sample of an adult general population (n=1000) was analyzed by upper endoscopy, duodenal biopsy, and serological analysis of tissue transglutaminase (tTg) levels; endomysial antibody (EMA) levels were analyzed in samples that were tTg+. The cutoff values for diagnosis of celiac disease were villous atrophy with 40 intraepithelial lymphocytes (IELs)/100 enterocytes (ECs).
Results
Samples from 33 subjects were tTg+ and 16 were EMA+. Histological analysis identified 7/1000 subjects (0.7%) with celiac disease; all were tTg+ and 6/7 were EMA+. Another 26 subjects were tTg+ (7/26 EMA+). This was addressed by a second quantitative pathology study, (nested case-control design) using a threshold of 25 IELS/100 ECs. In this analysis, all 13 samples that were tTg+ and EMA+ had ≥25 IELs/100ECs. In total, 16 subjects (1.6%) had serological and histological evidence of gluten-sensitive enteropathy. IELs were quantified in duodenal biopsy samples from seronegative individuals (n=500); 19 (3.8%) had >25 IELs and lymphocytic duodenosis (LD).
Conclusions
Measurement of ≥25 IELs/100 ECs correlated with serological indicators of celiac disease; a higher IEL threshold could miss 50% of cases. Quantification of tTg is a sensitive test for celiac disease; diagnosis can be confirmed by observation of ≥25 IELs/100ECs in duodenal biopsies. Lymphocytic enteropathy (celiac disease and LD) is common in the population (5.4%).
doi:10.1053/j.gastro.2010.04.007
PMCID: PMC2902605  PMID: 20398668
Celiac disease; Lymphocytic enteropathy; Serology; Histology; Epidemiology
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.  Fibromyalgia and non-celiac gluten sensitivity: a description with remission of fibromyalgia 
Rheumatology International  2014;34(11):1607-1612.
Fibromyalgia (FM) syndrome is a disabling clinical condition of unknown cause, and only symptomatic treatment with limited benefit is available. Gluten sensitivity that does not fulfill the diagnostic criteria for celiac disease (CD) is increasingly recognized as a frequent and treatable condition with a wide spectrum of manifestations that overlap with the manifestations of FM, including chronic musculoskeletal pain, asthenia, and irritable bowel syndrome. The aim of this report was to describe 20 selected patients with FM without CD who improved when placed on a gluten-free diet. An anti-transglutaminase assay, duodenal biopsy, and HLA typing were performed in all cases. CD was ruled out by negative anti-transglutaminase assay results and absence of villous atrophy in the duodenal biopsy. All patients had intraepithelial lymphocytosis without villous atrophy. Clinical response was defined as achieving at least one of the following scenarios: remission of FM pain criteria, return to work, return to normal life, or the discontinuation of opioids. The mean follow-up period was 16 months (range 5–31). This observation supports the hypothesis that non-celiac gluten sensitivity may be an underlying cause of FM syndrome.
doi:10.1007/s00296-014-2990-6
PMCID: PMC4209093  PMID: 24728027
Fibromyalgia; Celiac disease; Gluten sensitivity; Intraepithelial lymphocytosis
14.  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
15.  Antigliadin antibody in sporadic adult ataxia 
Iranian Journal of Neurology  2012;11(1):16-20.
Background
The most common neurologic manifestation of gluten sensitivity is ataxia, which accounts for up to 40% of idiopathic sporadic ataxia. Timing of diagnosis of gluten ataxia is vital as it is one of the very few treatable causes of sporadic ataxia and causes irreversible loss of Purkinje cells. Antigliadin antibody (AGA) of the IgG type is the best marker for neurological manifestations of gluten sensitivity. This study was conducted to measure the prevalence of gluten ataxia in a group of Iranian patients with idiopathic ataxia.
Methods
For 30 patients with idiopathic cerebellar ataxia, a questionnaire about clinical and demographic data was completed. Serum AGA (IgA and IgG) and antiendomysial antibody (AEA) were assessed. Gluten ataxic patients underwent duodenal biopsy. Magnetic resonance imaging was done for all patients to see if cerebellar atrophy is present.
Results
Only 2 patients had a positive IgG AGA (6.7%) who both had a positive AEA while none of them showed changes of celiac disease in their duodenal biopsies. Only presence of gastrointestinal symptoms and pursuit eye movement disorders were higher in patients with gluten ataxia.
Conclusion
Prevalence of gluten ataxia in Iranian patients with idiopathic ataxia seems to be lower than most of other regions. This could be explained by small sample size, differences in genetics and nutritional habits and also effect of serologic tests in clinical versus research setting. Further researches with larger sample size are recommended.
PMCID: PMC3829230  PMID: 24250853
Celiac Disease-Idiopathic Ataxia-Gluten Ataxia-Prevalence
16.  Celiac disease in the developing countries: A new and challenging public health problem 
In the past, celiac disease was believed to be a chronic enteropathy, almost exclusively affecting people of European origin. The availability of new, simple, very sensitive and specific serological tests (anti-gliadin, anti-endomysium and anti-transglutaminase antibody assays) have shown that celiac disease is common not only in Europe and in people of European ancestry but also in the developing countries where the major staple diet is wheat (Southern Asia, the Middle East, North West and East Africa, South America), both in the general population and in the groups at risk. Gluten intolerance thus appears to be a widespread public health problem and an increased level of awareness and clinical suspicion are needed in the New World where physicians must learn to recognize the variable clinical presentations (classical, atypical and silent forms) of celiac disease. In the developing countries, both serological screening in the general population and serological testing in groups at risk are necessary for an early identification of celiac patients. The gluten-free diet poses a challenging public health problem in the developing countries, especially since commercial gluten-free products are not available.
doi:10.3748/wjg.v13.i15.2153
PMCID: PMC4146836  PMID: 17465493
Celiac disease; Developing countries
17.  Alcohol Induces Sensitization to Gluten in Genetically Susceptible Individuals: A Case Control Study 
PLoS ONE  2013;8(10):e77638.
Background
The mechanisms of cerebellar degeneration attributed to prolonged and excessive alcohol intake remain unclear. Additional or even alternative causes of cerebellar degeneration are often overlooked in suspected cases of alcohol-related ataxia. The objectives of this study were two fold: (1) to investigate the prevalence of gluten-related serological markers in patients with alcohol-related ataxia and; (2) to compare the pattern of brain involvement on magnetic resonance imaging between patients with alcohol and gluten ataxias.
Materials & Methods
Patients diagnosed with alcohol and gluten ataxias were identified from a retrospective review of patients attending a tertiary clinic. HLA genotype and serological markers of gluten-related disorders were recorded. Cerebellar volumetry, MR spectroscopy and voxel-based morphometric analyses were performed on patients and compared with matched control data.
Results
Of 904 registered patients, 104 had alcohol ataxia and 159 had gluten ataxia. 61% of the alcohol ataxia group and 70% of the gluten ataxia group had HLA DQ2/DQ8 genotype compared to 30% in healthy local blood donors. 44% of patients with alcohol ataxia had antigliadin antibodies compared to 12% in the healthy local population and 10% in patients with genetically confirmed ataxias. None of the patients with alcohol ataxia and antigliadin antibodies had celiac disease compared to 40% in patients with gluten ataxia. The pattern of structural brain abnormality in patients with alcohol ataxia who had antigliadin antibodies differed from gluten ataxia and was identical to that of alcohol ataxia.
Conclusions
Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten. Such sensitization may result from a primary cerebellar insult, but a more systemic effect is also possible. The duration and amount of exposure to alcohol may not be the only factors responsible for the cerebellar insult.
doi:10.1371/journal.pone.0077638
PMCID: PMC3817350  PMID: 24204900
18.  Barriers impeding serologic screening for celiac disease in clinically high-prevalence populations 
BMC Gastroenterology  2014;14:42.
Background
Celiac disease is present in ~1% of the general population in the United States and Europe. Despite the availability of inexpensive serologic screening tests, ~85% of individuals with celiac disease remain undiagnosed and there is an average delay in diagnosis of symptomatic individuals with celiac disease that ranges from ~5.8-11 years. This delay is often attributed to the use of a case-based approach for detection rather than general population screening for celiac disease, and deficiencies at the level of health care professionals. This study aimed to assess if patient-centered barriers have a role in impeding serologic screening for celiac disease in individuals from populations that are clinically at an increased risk for celiac disease.
Methods
119 adults meeting study inclusion criteria for being at a higher risk for celiac disease were recruited from the general population. Participants completed a survey/questionnaire at the William K. Warren Medical Research Center for Celiac Disease that addressed demographic information, celiac disease related symptoms (gastrointestinal and extraintestinal), family history, co-morbid diseases and conditions associated with celiac disease, and patient-centered barriers to screening for celiac disease. All participants underwent serologic screening for celiac disease using the IgA tissue transglutaminase antibody (IgA tTG) and, if positive, testing for IgA anti-endomysial antibody (IgA EMA) as a confirmatory test.
Results
Two barriers to serologic testing were significant across the participant pool. These were participants not knowing they were at risk for celiac disease before learning of the study, and participants not knowing where to get tested for celiac disease. Among participants with incomes less than $25,000/year and those less than the median age, not having a doctor to order the test was a significant barrier, and this strongly correlated with not having health insurance. Symptoms and co-morbid conditions were similar among those whose IgA tTG were negative and those who tested positive.
Conclusion
There are significant patient-centered barriers that impede serologic screening and contribute to the delayed detection and diagnosis of celiac disease. These barriers may be lessened by greater education of the public and health care professionals about celiac disease symptoms, risk factors, and serologic testing.
doi:10.1186/1471-230X-14-42
PMCID: PMC4016507  PMID: 24592899
Celiac disease; Serologic screening; Barriers to screening
19.  Clinical features and symptom recovery on a gluten-free diet in Canadian adults with celiac disease 
BACKGROUND:
Celiac disease can present with mild or nongastrointestinal symptoms, and may escape timely recognition. The treatment of celiac disease involves a gluten-free diet, which is complex and challenging.
OBJECTIVE:
To evaluate clinical features and symptom recovery on a gluten-free diet in a Canadian adult celiac population.
METHODS:
All adult members (n=10,693) of the two national celiac support organizations, the Canadian Celiac Association and Fondation québécoise de la maladie coeliaque, were surveyed using a questionnaire.
RESULTS:
A total of 5912 individuals (≥18 years of age) with biopsy-confirmed celiac disease and/or dermatitis herpetiformis completed the survey. The female to male ratio was 3:1, and mean (± SD) age at diagnosis was 45.2±16.4 years. Mean time to diagnosis after onset of symptoms was 12.0±14.4 years. Abdominal pain and bloating (84.9%), extreme weakness/tiredness (74.2%), diarrhea (71.7%) and anemia (67.8%) were the most commonly reported symptoms at the time of diagnosis. Many respondents continued to experience symptoms after being on a gluten-free diet for >5 years. Sex differences were reported in clinical features before diagnosis, recovery after being on gluten-free diet and perceived quality of life, with women experiencing more difficulties than men.
CONCLUSIONS:
Delays in diagnosis of celiac disease in Canada remain unacceptably long despite wider availability of serological screening tests. Many patients report continuing symptoms despite adhering to a gluten-free diet for >5 years, with women experiencing more symptoms and a lower recovery rate than men. Awareness of celiac disease needs improvement, and follow-up with a physician and a dietitian is essential for all patients with celiac disease.
PMCID: PMC3956033  PMID: 23936873
Celiac disease; Cross-sectional study; Gluten-free diet; Recovery; Symptoms
20.  Evaluation of HLA-DQ2/DQ8 genotype in patients with celiac disease hospitalised in 2012 at the Department of Paediatrics 
Introduction
Celiac disease (CD) is a permanent intolerance to gluten that occurs in genetically predisposed individuals and leads to small intestinal mucosa damage. According to ESPGHAN guidelines from 2012, CD can be diagnosed in a patient with characteristic clinical symptoms, in whom, anti-tissue transglutaminase antibodies (> 10 times the upper limit) are found, endomysial antibodies (EMA) is confirmed and a positive genetic test is obtained. In these conditions no small-bowel biopsies are required.
Aim
Evaluation of the presence of HLA-DQ2 and HLA-DQ8 haplotypes in children with previously diagnosed CD, hospitalised in 2012 at the Department of Paediatrics and Immunology and/or the Gastroenterological Outpatient Clinic, and their relatives.
Material and methods
Blood samples of 22 subjects, including 9 children with CD diagnosed on the basis of clinical symptoms, serological investigations and small-intestine biopsy, 7 diagnosed on the basis of clinical symptoms and serological investigations, 2 with the suspicion of CD on the basis of clinical symptoms and 4 relatives of a child with CD. Methods: HLA-DQ2/DQ8 test, automatic evaluation by EUROArrayScan.
Results
The presence of HLA-DQ2 and/or HLA-DQ8 genotype was confirmed in 16 children with CD diagnosed on the basis of clinical symptoms and serological tests with/without intestinal biopsy, in 2 with the suspicion of CD and in 1 relative of a celiac child.
Conclusions
The evaluation of HLA-DQ2/DQ8 haplotype confirms the genetic predisposition to CD in subjects with the disease diagnosed previously on the basis of clinical symptoms, serological tests or intestinal biopsy. Genetic testing is particularly indicated for the diagnosis of CD in infants consuming gluten for a short time and in small amounts.
doi:10.5114/pg.2014.40848
PMCID: PMC4027840  PMID: 24868296
celiac disease; antibodies; genotype; inheritance
21.  Gluten sensitivity enteropathy in patients with recurrent aphthous stomatitis 
BMC Gastroenterology  2009;9:44.
Background
Gluten sensitive enteropathy (GSE) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in susceptible individuals. Recurrent aphthous stomatitis (RAS) may be the sole manifestation of GSE. The aim of this study was to determine the prevalence of gluten sensitivity enteropathy (GSE) in a large group of patients with RAS and assess the efficacy of gluten free diet (GFD) on the improvement of aphthous lesions in those who were diagnosed with GSE.
Methods
Two hundred and forty seven patients with RAS were included. The patients had at least three aphthous attacks per year. Patients were screened by IgA anti-endomysial antibody (EMA), IgA anti tissue transglutaminase (TTG) and serum IgA level. Those with a positive serology underwent endoscopic biopsies of the duodenal mucosa and patients with negative serology were excluded. The diagnosis of GSE was based on a positive serological test and abnormal duodenal histology. For patients with GSE, gluten free diet was recommended.
Results
Six out of 247 RAS patients had positive TTG test alone, and one had positive EMA and TTG. All 7 patients with positive serologic tests underwent duodenal biopsies. Histological findings were compatible with GSE in all of them (Marsh I in four patients, Marsh II in two patients and Marsh IIIB in one another.). The mean age of GSE patients was 27.42 ± 10.56 (range, 13 to 40) years old. They were suffering from RAS for an average duration of 4.5 years. All of the 7 GSE patients had not responded to the routine anti-aphthae medications, including topical corticosteroids, tetracycline and colchicine. Four patients who adhered to a strict gluten-free diet showed noticeable improvement in their aphthous lesions over a period of 6 months.
Conclusion
A significant minority (e.g. 2.83%) of RAS patients have GSE. This could be compared with the 0.9% prevalence of GSE in the general population of Iran. This study suggests that evaluation for celiac disease is appropriate in patients with RAS. Additionally, the unresponsiveness to conventional anti-aphthae treatment could be an additional risk indicator.
doi:10.1186/1471-230X-9-44
PMCID: PMC2709629  PMID: 19534771
22.  A new algorithm for the diagnosis of celiac disease 
Celiac disease (CD) affects at least 1% of the Western population but remains largely unrecognized. In our laboratory, we utilize a novel algorithm to diagnose pediatric CD that offers both high sensitivity and high specificity for diagnosis in an outpatient setting. The aim of the present study was to challenge this algorithm and to test its performance in children and adults suspected of having CD. Using a three-assay algorithm, screening with the most sensitive tissue transglutaminase (tTG) complexed with deamidated gliadin peptide neoepitope immunoglobulin A (IgA)+IgG assay and confirming with the two specific tTG IgA and tTG IgA+IgG assays, we examined the serological results from 112 children aged 0–17 years old and 60 adults in comparison to their respective biopsy results. The algorithm performance was calculated by statistical analysis. The use of the new algorithm enabled us to diagnose CD with 98% sensitivity, 93% specificity and 95% accuracy in the pediatric group and 94% sensitivity, 92% specificity and 93% accuracy in the total population studied. The false-negative cases in the adult group were attributed to previous adherence to a gluten-free diet, and the single false-negative result in a young child became a true positive after 6 months. We have also monitored three celiac patients before and after diagnosis and found that the algorithm may be suitable for disease monitoring. The newly proposed three-assay algorithm for celiac detection is very reliable in both children and adults. Due to the high performance of this assay, the further need for confirmatory intestinal biopsies will be reassessed.
doi:10.1038/cmi.2010.63
PMCID: PMC4003133  PMID: 21317919
celiac disease diagnosis; intestinal histopathology; sensitivity; specificity; tissue transglutaminase
23.  Celiac disease in South-West of Iran 
AIM: Celiac disease is characterized by life-long gluten intolerance. Clinical features of patients with celiac disease are variable. Studies about the prevalence of celiac disease in our country are scarce and there is no study on the prevalence of celiac disease in southern Iran. In the current study, clinical, laboratory and histo-logical features of 52 patients with celiac disease were evaluated.
METHODS: In a cross sectional study we retrospectively studied the characteristics of 52 celiac patients at Ahwaz JundiShapour University Hospitals (AJSUH) from November 1, 1999 to 1st Sep 2004. Intestinal biopsy and serum antigliadin and anti-endomysium antibodies were used for the diagnosis of patients. Mucosal lesions were classified according to the criteria of Marsh. Antigliadin antibodies were measured with a commercial enzyme-linked immunosorbent assay. Anti-endomysium antibodies were analyzed by indirect immunofluorescence with the use of a section of monkey esophagus. Routine hematological and biochemical analyses and measurement of immunoglobulin levels were undertaken.
RESULTS: Male: female ratio was 1.08. The mean ± SD patient age was 21 ± 4.5 years (range 10-70 years) and the most common symptoms were diarrhea and weight loss (78.8%) followed by fatigue (73.1%), pallor (65.4%), anorexia (40.4%), abdominal distention (32.7%), and failure to thrive (23.1%). Diarrhea and weight loss and fatigue were the most common findings. Iron deficiency anemia was found in 63.2% of patients and this became normal after adoption of a gluten-free diet in all patients. Immunoglobulin A, IgG antigliadin antibodies and IgA anti-endomysium antibodies were found in 33 and 48 cases, 78.8% and 85.4% of patients, respectively. Biopsy of the small intestine revealed that 90.4% of patients had typical lesions according to the Marsh classification.
CONCLUSION: Although classical presentation was seen in most of the patients, atypical clinical manifestations of celiac disease should be kept in mind. In particular, patients with uncommon findings, such as short stature, and iron-deficiency anemia, should be screened for celiac disease. Further epidemiological studies in our area in the general population and in high risk groups seem to be indicated.
doi:10.3748/wjg.v12.i27.4416
PMCID: PMC4087758  PMID: 16865789
Celiac disease; IgG endomysial autoantibodies; Southern Iran
24.  Prevalence of celiac disease in Germany: A prospective follow-up study 
AIM: To determine the prevalence of celiac disease in a randomly selected population sample.
METHODS: A total of 2157 subjects (1036 males; 1121 females) participating in a population-based cross-sectional study underwent laboratory testing for tissue transglutaminase and antibodies to immunoglobulin A, endomysium and antigliadin. In a second step, all subjects who had been examined serologically were surveyed using a questionnaire that included questions specific to celiac disease. Subjects with positive antibody titers and those with histories positive for celiac disease then underwent biopsy. At the first follow up, antibody titers were again determined in these subjects and subjects were questioned regarding symptoms specific for celiac disease and disorders associated with celiac disease. The second follow up consisted of a telephone interview with subjects positive for celiac disease.
RESULTS: Antibody tests consistent with celiac disease were reported in eight subjects, corresponding to an overall prevalence of 1:270 (8/2157). The prevalence among women was 1:224 and 1:518 in men. Classical symptoms were observed in 62.5% of subjects. Atypical celiac disease was present in 25.0%, and transient celiac disease in 12.5%. False-negative test results were returned in three subjects. This yields a sensitivity and specificity of 62.5% and 50.0%, respectively, for tissue transglutaminase immunoglobulin-A antibody; of 62.5% and 71.4% respectively, for endomysium antibody; and of 62.5% and 71.4%, respectively, for antigliadin antibody.
CONCLUSION: The prevalence rate in our collective lies within the middle tertile of comparable studies in Europe. The use of a single antibody test for screening purposes must be called into question.
doi:10.3748/wjg.v19.i17.2612
PMCID: PMC3645379  PMID: 23674868
Cross-sectional study; Celiac disease; Screening; Prevalence; Serology
25.  Lymphocytic Duodenosis and the Spectrum of Celiac Disease 
Introduction:
Celiac disease (CD) is a chronic inflammatory disease of the small bowel that is characterized by increased intraepithelial lymphocytes (IELs) and villous atrophy of the mucosa. It is unclear how often intraepithelial lymphocytosis in the absence of atrophy is a manifestation of gluten sensitive enteropathy. The objective of this study was to identify factors that discriminate patients with celiac disease from those with lymphocytic duodenosis (intraepithelial lymphocytosis without villous atrophy). We compared Class 2 HLA type, presenting symptoms, and serology in patients with lymphocytic duodenosis (LD) and CD.
Methods:
Retrospective review of 124 systematically assessed patients with LD compared with 454 CD patients with villous atrophy. All patients had duodenal biopsies and Class 2 HLA typing performed. HLA type, symptoms, serology pattern, and response to a gluten free diet were analyzed using univariate logistic regression modeling, adjusted for age and gender.
Results:
Half of the (63 [51%]) LD patients lack the Class 2 HLA genotypes encoding DQ2 or DQ8 whereas only 11 (2%) CD patients had neither DQ2 nor DQ8, p<0.001. The genes encoding DQ2 were much more prevalent in CD (91%) than that in LD (37%, p<0.001), however, the rate of carriage of DQ8 did not differ between the two groups (15% versus 15%, p=0.9). While diarrhea and weight loss were equally frequent in both LD and CD patients, LD patients were less likely to be associated with anemia (p=0.007), malaise (p=0.006), skin disorder (p=0.007), or a family history of celiac disease (p<0.001). The LD subjects were much less likely to have tissue transglutaminase or endomysial antibodies than CD (12% or 0% versus 87% and 87%; p<0.001 respectively).
Conclusion:
The LD cohort differs significantly in terms of HLA type, serology and clinical features, suggesting that the majority of patients with lymphocytic duodenosis do not belong in the spectrum of celiac disease.
doi:10.1038/ajg.2008.7
PMCID: PMC2608723  PMID: 19098862
sprue; genetics; HLA; pathology

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