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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.  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
3.  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
4.  Are Hepatitis B Virus and Celiac Disease Linked? 
Hepatitis Monthly  2010;10(3):173-175.
Background and Aims
It has been hypothesized that nonintestinal inflammatory diseases such as hepatitis B virus (HBV) and hepatitis C virus (HCV) may trigger immunologic gluten intolerance in susceptible people. This hypothesis suggests a possible epidemiological link between these two diseases, although this assumption is still a matter of debate.
Methods
We conducted a retrospective study to assess the prevalence of celiac disease in HBV carrier patients who had been infected in childhood.
Results
None of the HBV carrier patients had immunoglobulin A antiendomysium and immunoglobulin A anti-tissue transglutaminase, but 6 patients and 1 recovered subject had immunoglobulin A antigliadin and/or immunoglobulin G antigliadin. Moreover, no patient treated with interferon therapy showed any serological marker of celiac disease.
Conclusions
Due to the small sample size, we cannot claim that there is no association between celiac disease (CD) and HBV, although in our study we did not find any CD patients. A sample size that is more representative of the prevalence of CD in Italy would better support the establishment of any possible connection between CD and HBV.
PMCID: PMC3269080  PMID: 22308135
Hepatitis B Virus; Celiac Disease; Enteropathy
5.  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
6.  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
7.  Comparative Usefulness of Deamidated Gliadin Antibodies in the Diagnosis of Celiac Disease 
Background & Aims
Serologic tests are frequently used in celiac disease diagnosis. Gliadin antibodies generally lack the accuracy required for proper diagnosis. We evaluated the value of deamidated gliadin antibody measurements in the diagnosis and follow-up of celiac disease and compared their potential usefulness with that of gliadin and tissue-transglutaminase antibodies.
Methods
We tested deamidated gliadin, gliadin, and tissue-transglutaminase-IgA and -IgG in 216 biopsy-selected subjects including 92 biopsy-proven untreated celiac patients (46% with total villous atrophy and 54% with partial villous atrophy) and 124 biopsy-proven non-celiac controls. Fifty-nine of celiac patients were also tested after treatment with gluten-free diet. Antibodies were measured by commercial enzyme-linked immunosorbent assays. Deamidated gliadin-IgA+G was detected using a conjugate reactive to both isotypes which gives a positive if either isotype is present.
Results
The sensitivity, specificity, and accuracy of deamidated gliadin-IgA (74%, 95%, and 86%), deamidated gliadin-IgG (65%, 98%, and 84%) and deamidated gliadin-IgA+G (75%, 94%, and 86%) were superior to gliadin-IgA (63%, 90%, and 79%) (P < 0.05) and gliadin-IgG (42%, 90%, and 69%) (P < 0.01) and were similar to tissue-transglutaminase-IgA (78%, 98%, and 90%) before treatment. The sensitivity of IgA isotype for all tests was significantly greater in celiac patients with total villous atrophy compared to those with partial villous atrophy (P < 0.05). The proportion of positive test results for all tests decreased significantly after treatment (P < 0.0001).
Conclusions
Deamidated gliadin antibody is a better diagnostic test for celiac disease than the conventional gliadin antibody testing; although histopathology remains the gold standard test for diagnosis of celiac patients.
doi:10.1016/j.cgh.2007.12.030
PMCID: PMC2440671  PMID: 18304884
8.  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
9.  Update on celiac disease – etiology, differential diagnosis, drug targets, and management advances 
Celiac disease (CD) is an immune-mediated enteropathy triggered by exposure to wheat gluten and similar proteins found in rye and barley that affects genetically susceptible persons. This immune-mediated enteropathy is characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Once thought a disease that largely presented with malnourished children, the wide spectrum of disease activity is now better recognized and this has resulted in a shift in the presenting symptoms of most patients with CD. New advances in testing, both serologic and endoscopic, have dramatically increased the detection and diagnosis of CD. While the gluten-free diet is still the only treatment for CD, recent investigations have explored alternative approaches, including the use of altered nonimmunogenic wheat variants, enzymatic degradation of gluten, tissue transglutaminase inhibitors, induction of tolerance, and peptides to restore integrity to intestinal tight junctions.
doi:10.2147/CEG.S8315
PMCID: PMC3254208  PMID: 22235174
immune-mediated enteropathy; gliadin; gluten; epidemiology; CD diagnosis; therapy
10.  A trichobezoar in a child with undiagnosed celiac disease: A case report 
Celiac disease is a chronic, immune-mediated enteropathy caused by a permanent sensitivity to ingested gluten cereals that develops in genetically susceptible individuals. The classic presentation of celiac disease includes symptoms of malabsorption but has long been associated with cognitive, emotional, and behavioral disorders. We describe an 8-year-old patient with non-scarring alopecia and diagnosed with trichotillomania. Furthermore, she presented with a 3-year history of poor appetite and two or three annual episodes of mushy, fatty stools. Laboratory investigations showed a normal hemoglobin concentration and a low ferritin level. Serologic studies showed an elevated tissue immunoglobulin G anti-tissue transglutaminase level. A duodenal biopsy showed subtotal villous atrophy and crypt hyperplasia, and a large gastric trichobezoar was found in the stomach. Immediately after beginning a gluten-free diet, complete relief of trichotillomania and trichophagia was achieved. In this report, we describe a behavioral disorder as a primary phenomenon of celiac disease, irrespective of nutritional status.
doi:10.3748/wjg.v20.i5.1357
PMCID: PMC3921519  PMID: 24574811
Celiac disease; Trichobezoar; Trichotillomania; Behavioral disorder; Malabsorption syndrome
11.  Positive celiac disease serology and reduced bone mineral density in adult women 
BACKGROUND:
Low bone density and osteoporosis have been demonstrated in celiac disease populations in Europe, South America and the United States. Serological testing with tissue transglutaminase (TTG) and immunoglobulin A endomysial (EMA) antibodies is highly specific for celiac disease, while antigliadin antibody (AGA) testing is less specific.
OBJECTIVE:
To evaluate the association of celiac serology with reduced bone density in adult women.
METHODS:
A clinical database containing all bone density testing data in the province of Manitoba was linked to a database containing all celiac serology data for the province. The study cohort consisted of 376 women older than 20 years of age with bone density measurements preceding initial celiac serology by six months or less. Bone density was assessed in relation to TTG/EMA and AGA seropositivity, and compared with seronegative controls in age-, height- and weight-adjusted models.
RESULTS:
There was significantly lower bone density in TTG/EMA seropositive women than with seronegative controls for all sites tested (lumbar spine, total hip, trochanter, femoral neck; all P<0.05). TTG/EMA seropositive women also had a significantly higher prevalence of osteoporosis (67.7% versus 44.8%; P<0.05). There was lower bone density at the three hip sites (all P<0.05) in AGA seropositive women, but after excluding TTG/EMA seropositive women, isolated AGA seropositivity showed no significant association with any bone density measurements.
CONCLUSION:
TTG/EMA seropositivity was associated with lower bone density and a higher prevalence of osteoporosis compared with seronegative controls.
PMCID: PMC2852231  PMID: 20151068
Bone density; Celiac disease; Celiac serology; Osteoporosis
12.  Serology of celiac disease in gluten sensitive ataxia or neuropathy; Role of deamidated gliadin Antibody 
Journal of neuroimmunology  2010;230(1-2):130-134.
The role and relevance of deamidated gliadin antibodies specific for celiac disease in gluten-sensitive ataxia/ neuropathy is unknown. We investigated the association of celiac-specific serology with gluten-sensitive ataxia/neuropathy, in patients with and without gliadin-induced enteropathy. 51 patients with unexplained ataxia/neuropathy suspected to have gluten sensitivity were included in the study and their serum celiac specific markers were measured. Deamidated-gliadin-IgA (83% vs 22%), deamidated-gliadin-IgG (50% vs 3%), tissue-transglutaminase-IgA (78% vs 11%), and anti-endomysial-IgA (70% vs 0%), were significantly more positive in ataxia/neuropathy patients with celiac disease versus those without enteropathy (P <0.001). Our findings suggest that the serological profile of gluten-sensitive ataxia/neuropathy without intestinal involvement lacks the recognition of deamidated-gliadin and tissue-transglutaminase epitopes.
doi:10.1016/j.jneuroim.2010.09.024
PMCID: PMC3092384  PMID: 21056914
Ataxia; Neuropathy; Gluten sensitivity; Celiac disease; Deamidated gliadin Antibody
13.  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
14.  Celiac disease: an underappreciated issue in women’s health 
Women's health (London, England)  2010;6(5):753-766.
Celiac disease (CD) is an immune-mediated enteropathy that is secondary to gluten ingestion and classically associated with gastrointestinal symptoms. Diagnosis is based on serology and confirmatory duodenal biopsy, and the only treatment is lifelong avoidance of gluten. CD has been increasingly recognized to encompass a wide variety of manifestations that are relevant to women’s health, including infertility, adverse pregnancy outcomes and reduced BMD. Currently, CD is underdiagnosed, largely owing to lack of recognition of the diverse manifestations by general practitioners. Increased awareness of the clinical spectrum of this disease, as well as targeted testing in at-risk individuals (including women with unexplained infertility and previous adverse pregnancy outcomes, and in specific populations with reduced BMD) is greatly needed in order to improve rates of diagnosis.
doi:10.2217/whe.10.57
PMCID: PMC3046043  PMID: 20887172
bone-density celiac disease; fertility; gluten; osteopenia; osteoporosis; pregnancy; screening; tissue transglutaminase
15.  Dietary treatment of gluten ataxia 
Background: Gluten ataxia is an immune mediated disease, part of the spectrum of gluten sensitivity, and accounts for up to 40% of cases of idiopathic sporadic ataxia. No systematic study of the effect of gluten-free diet on gluten ataxia has ever been undertaken.
Objective: To study the effect of gluten-free diet on patients presenting with ataxia caused by gluten sensitivity.
Methods: 43 patients with gluten ataxia were studied. All were offered a gluten-free diet and monitored every six months. All patients underwent a battery of tests to assess their ataxia at baseline and after one year on diet. Twenty six patients (treatment group) adhered to the gluten-free diet and had evidence of elimination of antigliadin antibodies by one year. Fourteen patients refused the diet (control group). Three patients had persistently raised antigliadin antibodies despite adherence to the diet and were therefore excluded from the analysis.
Results: After one year there was improvement in ataxia reflected in all of the ataxia tests in the treatment group. This was significant when compared with the control group. The diet associated improvement was apparent irrespective of the presence of an enteropathy.
Conclusions: Gluten ataxia responds to a strict gluten-free diet even in the absence of an enteropathy. The diagnosis of gluten ataxia is vital as it is one of the very few treatable causes of sporadic ataxia.
doi:10.1136/jnnp.74.9.1221
PMCID: PMC1738682  PMID: 12933922
16.  Effectiveness of antigliadin antibodies as a screening test for celiac disease in children 
OBJECTIVE: To test the effectiveness of serologic antigliadin antibody (AGA) testing in predicting celiac disease in children. DESIGN: Prospective clinical assessment. SETTING: Hôpital Sainte-Justine, montreal. PATIENTS: A total of 176 children with possible celiac disease who were referred for duodenal biopsy between January 1992 and June 1995. OUTCOME MEASURES: IgA and IgG AGA titres, as determined by enzyme-linked immunosorbent assay (ELISA); duodenal biopsy; clinical outcome on a gluten-free diet. RESULTS: Of the 176 children 30 were found to have celiac disease according to the criteria of the European Society of Pediatric Gastroenterology and Nutrition (ESPGAN). The sensitivity and specificity of the IgA AGA titre, as well as its positive and negative predictive values, were 80%, 92%, 67% and 96% respectively; the corresponding values for the IgG AGA titre were 83%, 79%, 45% and 96%. The respective values for IgA and IgG AGA titres combined were 93%, 71%, 43% and 98%. Only 2 of the 30 patients with celiac disease had false-negative results for both IgA and IgG AGA titres. The IgA and IgG AGA titres decreased significantly (p < 0.005) in all 11 patients after being on a gluten-free diet for at least 10 months and reached normal values in 8. CONCLUSION: AGA screening for celiac disease permits better selection of patients for duodenal biopsy and adds specificity to the histologic diagnosis. Such screening cannot replace intestinal biopsy, which remains the gold standard for diagnosis.
PMCID: PMC1227966  PMID: 9294391
17.  Testing for Antireticulin Antibodies in Patients with Celiac Disease Is Obsolete: a Review of Recommendations for Serologic Screening and the Literature 
Celiac disease (CD) is an autoimmune disorder that occurs in genetically susceptible individuals of all ages and is triggered by immune response to gluten and related proteins. The disease is characterized by the presence of HLA-DQ2 and/or -DQ8 haplotypes, diverse clinical manifestations, gluten-sensitive enteropathy, and production of several autoantibodies of which endomysial, tissue transglutaminase, and deamidated gliadin peptide antibodies are considered specific. Although antireticulin antibodies (ARA) have historically been used in the evaluation of CD, these assays lack optimal sensitivities and specificities for routine diagnostic use. This minireview highlights the advances in CD-specific serologic testing and the rationale for eliminating ARA from CD evaluation consistent with recommendations for diagnosis.
doi:10.1128/CVI.00568-12
PMCID: PMC3623418  PMID: 23365209
18.  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
19.  Serological Responses to Microbial Antigens in Celiac Disease Patients During a Gluten-Free Diet 
Journal of clinical immunology  2008;29(2):190-195.
Background
Immunoglobulin A (IgA) autoantibodies to tissue transglutaminase (tTG) are commonly used for screening and diagnosing of celiac disease (CD). Seroreactivity for anti-Saccharomyces cerevisiae antibody (ASCA) and bacterial antigens have also been detected in CD patients. The aim of this study was to examine prospectively serologic responses to microbial targets in adult CD patients at the time of diagnosis and during a gluten-free diet (GFD). Further, we wanted to evaluate whether these serologic specificities could provide new tools for the follow-up of CD patients.
Methods
Data on 55 adult biopsy-proven CD patients were available for follow-up study. Upper gastrointestinal endoscopy was performed on all patients. Sera from patients were tested for antibodies to tTG and ASCA and additionally analyzed with IgA enzyme-linked immunosorbent assays to Pseudomonas fluorescens-associated sequence, I2, and to a Bacteroides caccae TonB-linked outer membrane protein, OmpW.
Results
At the time of diagnosis, 91% of CD cases were positive for tTG and 49% for ASCA; positive seroreactivity to I2 was found in 86% and to OmpW in 60% of CD patients at the time of diagnosis. The frequency of seropositivity and serum levels of these antibodies decreased during GFD. Moreover, we found that the decline in the serum levels was significant in all of these markers (p<0.005). Interestingly, we also found that serum levels of ASCA correlated with the grade of mucosal morphology (p=0.021), as the ASCA serum levels declined in accordance with mucosal healing.
Conclusions
Commensal enteric bacteria seem to play a role in the small intestinal mucosal damage in CD. This was proven by the serological responses to different microbial antigens shown in this study. Serum levels of ASCA, anti-I2, and anti-OmpW antibodies decreased significantly during GFD, indicating that these serologic markers are gluten dependent in CD patients. These specificities could provide new tools in the follow-up of CD patients.
doi:10.1007/s10875-008-9255-7
PMCID: PMC3770459  PMID: 18987962
Celiac disease; gluten-free diet; ASCA; I2; OmpW
20.  Visualization of Transepithelial Passage of the Immunogenic 33-Residue Peptide from α-2 Gliadin in Gluten-Sensitive Macaques 
PLoS ONE  2010;5(4):e10228.
Background
Based on clinical, histopathological and serological similarities to human celiac disease (CD), we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from α2-gliadin in the distal duodenum of gluten-sensitive macaques.
Methodology/Principal Findings
Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with “leaky” duodenum, the peptide penetrated beneath the epithelium into the lamina propria.
Conclusions/Significance
The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.
doi:10.1371/journal.pone.0010228
PMCID: PMC2856682  PMID: 20419103
21.  New and Developing Therapies for Celiac Disease 
The treatment for celiac disease, a removal of gluten in the diet, is safe and effective for the vast majority of patients. There is a large body of evidence that the diagnosis and treatment of those with celiac disease ensures considerable health benefits. Although a gluten-free diet is the principal treatment for celiac disease, it is relatively expensive, inconvenient and difficult to adhere to. For these reasons, there is interest in developing alternative therapies. Emerging research for the treatment of celiac disease has focused on three areas: to decrease gluten exposure, to modify intestinal permeability and to modulate immune activation. Therapies developed thus far consist of enzymes designed to digest gluten and the use of inhibitors of paracellular permeability to decrease the migration of gluten peptides into the lamina propria. Other potential therapeutic maneuvers include the binding of gluten by polymers, the use of tissue transglutaminase (TTG) inhibitors and DQ2 or DQ8 blockers, or modulation of cytokine production. While all represent new and exciting therapies, an ideal therapy should have virtually no side effects similar to a gluten-free diet. A pharmaceutical agent may be used on an intermittent basis, such as following occasional gluten exposure or on a chronic basis to mitigate the effects of potential inadvertent ingestion of gluten.
doi:10.1177/1756283X09342759
PMCID: PMC3002532  PMID: 21180558
celiac disease; gluten; gliadin; prolyl endopeptidases; therapy
22.  Serologic Testing for Celiac Disease in the United States: Results of a Multilaboratory Comparison Study 
The aim of this study was to compare the efficiencies of six reference laboratories for serologic testing for celiac disease. Serum from 20 patients with untreated celiac disease and from 20 controls was thawed, divided, and distributed to each participating laboratory, which performed endomysial antibody tests. Five laboratories also performed antigliadin antibody tests. Sensitivity for endomysial antibody immunoglobulin A (IgA) varied from 57 to 90%. In all laboratories, the specificity for celiac disease was 100%. The sensitivity and specificity for both IgA and IgG antigliadin antibody varied significantly. When results from all three tests were combined in each laboratory, sensitivity was 90 to 100%. The specificity for endomysial antibody was 100% in the laboratories. Sensitivity was less than reported previously. Standardization of these tests is needed in the United States.
PMCID: PMC95918  PMID: 10882656
23.  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
24.  Frequency of Celiac Disease in Patients with Hypothyroidism 
Journal of Thyroid Research  2012;2012:201538.
Background. Celiac disease (CD) is closely associated with other autoimmune endocrine disorders, particularly autoimmune thyroid disease. The aim of this study was to find the frequency of celiac disease in patients with hypothyroidism in Guilan province, north of Iran. Methods. A total of 454 consecutive patients with hypothyroidism underwent celiac serological tests antiGliadin antibodies (AGA), antitissue transglutaminase antibodies (IgA-tTG) and antiendomysial antibodies (EMA-IgA). Small intestinal biopsy was performed when any of celiac serological tests was positive. Results. Eleven (2.4%) patients were positive for celiac serology, and two patients with documented villous atrophy were diagnosed with classic CD (0.4%; 95%). Two patients with classic CD had Hashimoto's thyroiditis (HT) (0.6%; 95%). Six (54.5%) of 11 were suffering from overt hypothyroidism and 45.5% from subclinical hypothyroidism. Six (54.5%) had HT, and 45.5% had nonautoimmune hypothyroidism. Conclusions. In this study, prevalence of CD was lower than other studies. Most of the patients with CD were suffering from HT, but there was no significant statistical relation between CD and HT.
doi:10.1155/2012/201538
PMCID: PMC3321550  PMID: 22545223
25.  Between Celiac Disease and Irritable Bowel Syndrome: The “No Man’s Land” of Gluten Sensitivity 
The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.
doi:10.1038/ajg.2009.188
PMCID: PMC3480312  PMID: 19455131

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