Specificity For Celiac Disease Research Articles

Evolution in coeliac disease diagnosis and management.

The traditional gut-centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease - well demonstrated in children - are growing for adults. Novel biomarkers such as interleukin-2 that identify the gluten-specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge. Asymptomatic disease and manifestations outside the gut pose considerable challenges for diagnosis using a case-finding strategy and enthusiasm for population screening is growing. The gluten-free diet remains a highly restrictive treatment and there is a paucity of controlled data to inform a safe gluten intake threshold. Ongoing symptoms and enteropathy are common and require systematic evaluation. Slowly-responsive disease is prevalent in the older patient diagnosed with coeliac disease, and super-sensitivity to gluten is an emerging concept that may explain many cases of nonresponsive disease. While there is great interest in developing novel therapies for coeliac disease, no drug has yet been registered. Efficacy studies are generally assessing drugs in patients with treated coeliac disease who undergo gluten challenge or in patients with nonresponsive disease; however, substantial questions remain around specific endpoints relevant for patients, clinicians and regulatory agencies and optimal trial design. Novel immune tools are providing informative readouts for clinical trials and are now shaping their design.

Point-of-care testing for coeliac disease: primary care diagnostic technology update

#### Clinical Question In primary care patients with suspected coeliac disease, what is the accuracy and utility of point-of-care (POC) testing for coeliac disease compared to standard practice? Coeliac disease is a malabsorption syndrome precipitated by gluten ingestion, and characterised by inflammation of the small intestine. Serological tests for IgA anti-tissue transglutaminase antibody (tTGA) and anti-endomysial antibody (EMA) have high sensitivity and specificity for coeliac disease.1,2 In patients with IgA deficiency, the IgG class of the tTGA and EMA tests are recommended. Anti-gliadin antibodies are no longer used for the detection of coeliac disease, except in children younger than 18 months.2 Conventional serological tests are performed in central laboratories, whereas the point-of-care (POC) test can be performed in practice or at home. Both the POC and conventional serological tests require patients to be on a normal gluten-containing diet at the time of testing, since IgA-tTGA titres diminish on a gluten-free diet. Two POC devices available on the market were identified. ### Biocard Coeliac Test Kit (Ani Biotech, Finland; UK Distributor: BHR Pharmaceuticals Ltd) There are two versions of the test, a home test and a professional test; a ‘total IgA measuring system’ is included in the professional kit. The Biocard requires a drop of whole blood (finger-prick) and provides results within 10 minutes. Anti-tTG IgA antibodies bind to antigen in the test strip to form a visible line. A positive test result shows two lines, while only one line appears if the test is negative. If there is no line, IgA deficiency should be suspected. ### Stick CD1 and CD2 (Operon SA, Zaragoza, Spain) Both are one-step tests detecting IgA, IgG, and IgM antibodies against human tTG; and the CD2 test also detects anti-gliadin antibodies. The tests use serum instead of whole blood, which limits …

Duodenal Intraepithelial Lymphocytosis With Normal Villous Architecture in Pediatric Patients

Small bowel intraepithelial lymphocytosis (IELs) with normal villous architecture is a relatively common finding, often of uncertain significance. The aims of our study were to determine the prevalence of this finding, its clinical associations, its specificity for celiac disease (CD), and whether histologic clues exist that increase the specificity for CD in this setting, all in the pediatric population. The Mayo Clinic electronic pathology database was searched between January 1, 2000 and December 31, 2009 for patients younger than 18 years who had the terms "normal villi" and "increased intraepithelial lymphocytes" in their small bowel biopsy reports. All of the slides were reviewed to confirm the histologic findings. Demographic, serologic, pathologic, and clinical informations were obtained. Among 1290 duodenal biopsies obtained from children during the years 2000 and 2009, 56 (4.3%) were noted to have "normal villous architecture with increased intraepithelial lymphocytes." In the 54 patients not known to have CD before biopsy, 48 (89%) had serologic testing for CD. Of these 48 patients, 9 were labeled with CD, although only 5 of 9 met the definite criteria for the diagnosis, based on a combination of serologic markers, human leukocyte antigen haplotyping, and response to gluten-free diet. No clinical features pointed to a diagnosis of CD. There was no correlation between CD and number of IELs, but patients with newly diagnosed CD were more likely to have a tip-heavy lymphocyte distribution. Other diagnoses made during the study period and in follow-up were inflammatory bowel disease (5), Helicobacter pylori infection (3), medication-related injury (10), and systemic autoimmune disorders (2). Increased IELs with normal villous architecture in small bowel biopsies are clinically important in children, and are associated with a new definite diagnosis of CD in 9% of pediatric patients. Even at this low sensitivity, clinical work-up for CD is mandated in all of the patients with this finding.

Intestinal deposits of anti-tissue transglutaminase IgA in childhood celiac disease

Background High serum levels of anti-tissue-transglutaminase-2 IgA antibodies (anti-TG2), which are produced and deposited in the intestine, characterize celiac disease. Aim To assess the diagnostic value of intestinal deposits of anti-TG2 IgA for celiac disease in a paediatric population. Methods 344 children underwent duodenal biopsy for the suspicion of CD, and were divided into 3 groups: group A, 144 celiac subjects with villous atrophy (Marsh 3b–c); group B, 109 subjects with high serum levels of anti-TG2 but normal intestinal mucosa (Marsh 0–1) (potential celiac disease patients); group C, 91 subjects with normal levels of serum anti-TG2: 70 with Marsh 0–1 and 21 with Marsh 3a mucosa. All duodenal sections were evaluated for the presence of intestinal deposits of anti-TG2 IgA by double immunofluorescence. Results Deposits of anti-TG2 IgA were present in 96%, 68%, 12% of patients from groups A, B, C, respectively. Diagnostic sensitivity and specificity for celiac disease were 96% and 88% vs. 97% and 100% for serum anti-TG2, respectively. The degree of concordance with serum anti-TG2 was 85%. Conclusion Detection of intestinal deposits of anti-TG2 IgA is a useful diagnostic tool. Further research is needed regarding their ability to predict evolution to villous atrophy in potential celiac disease.

Positive serum antigliadin antibodies without celiac disease in the elderly population: does it matter?

Objective. Antigliadin antibodies (AGA) show good sensitivity but low specificity for celiac disease and can also be found in healthy individuals. However, data suggest that AGA positivity might be related to distinct disease entities such as allergy and gluten ataxia. Our aim here is to explore the clinical relevance of positive AGA in the elderly population. Material and methods. Serum IgA- and IgG-class AGA and IgA-class tissue transglutaminase antibodies (tTGA) were determined in 2815 individuals aged 52–74 years. Equal numbers of AGA- and tTGA-negative participants of similar age and gender, but without known celiac disease, were randomly selected as controls. Information on clinical history was obtained from hospital records in all groups. Results. Altogether 381 persons were positive for IgA/IgG-class AGA; 38 (14%) of them were also positive for tTGA. Out of the biopsied subjects, 34 (100%) in the AGA+ tTGA+ group and five (9%) in AGA+ tTGA− group had celiac disease. Rheumatoid arthritis and depression were found significantly more often in AGA-positives than controls. The significance remained even when tTGA-positive and known celiac disease cases were excluded. No statistical differences were found in the occurrence of neurological diseases, diabetes, allergic and cardiovascular diseases or malignancies. Conclusions. Although AGA positivity is of clinical relevance only in a subset of elderly people, it seems to be related to rheumatoid arthritis and depression, both conditions linked to celiac disease. Further studies are needed to reveal the mechanisms underlying this. The poor specificity of AGA for celiac disease was here once more in evidence.

Small intestine capsule endoscopy in the diagnostics of coeliac disease

Coeliac disease is an autoimmune enteropathy precipitated by the gluten content of cereals. It had for long been considered a childhood condition as clinical symptoms manifested when gluten was introduced into the diet. The introduction of specific serological markers changed our understanding of the epidemiology and semiology of the syndrome. The main difficulty of the diagnostics arises from the fact that over 50% of patients with gluten-sensitive enteropathy show atypical symptoms, while coeliac-disease patients with extra-gastrointestinal manifestations show no gastrointestinal symptoms at all. Diagnostics of coeliac disease is currently based on the detection of specific antibodies and the histological assessment of the duodenum. Macroscopic signs of villous atrophy (reduction in the number or loss of Kerking's folds, vascular pattern visible through the mucosa, "mosaic or micronodular" pattern, "scalloped" folds) are clearly visible in untreated patients. Capsule endoscopy, contrary to conventional endoscopic approaches, enables non-invasive, pain-free investigation of the entire small intestine. Duodenal mucosa is visualised at an 8:1 magnification during the investigation, enabling the assessment of villous atrophy by an experienced investigator. Based on preliminary experience, standard upper tract endoscopy and capsule endoscopy appear to exhibit equal levels of sensitivity and specificity for coeliac disease. The advantage of CE versus upper tract endoscopy lies in the complete assessibility of the small intestine, thus also enabling the assessment of the spread and severity of the disease. The disadvantage associated with the approach is the lack of histological biopsy samples. CE is recommendable as a first line approach for patients with proven coeliac disease when alarm conditions appear.

Usefulness of Antibodies to Deamidated Gliadin Peptides in Celiac Disease Diagnosis and Follow-up

The prevalence of the recently described deamidated gliadin peptide antibodies was compared with that of the routinely used antigliadin, antiendomysial, and tissue transglutaminase antibodies in the sera of 128 untreated celiac patients and 134 controls. Sensitivity and specificity for celiac disease were 83.6 and 90.3% for IgA and 84.4 and 98.5% for IgG antibodies to deamidated gliadin peptides. The new test displayed higher diagnostic accuracy than antigliadin antibodies and, although less sensitive than antiendomysial and tissue transglutaminase antibodies, showed significantly higher specificity than tissue transglutaminase antibodies (P < 0.001). Persistence of peptide antibodies after gluten withdrawal was an expression of low compliance with the diet and of the lack of improvement of the intestinal mucosa. The combined use of tissue transglutaminase and deamidated gliadin peptide antibodies seems to be a very useful tool for celiac disease diagnosis. Moreover, antibodies to deamidated gliadin peptides can be helpful in disease follow-up.

Preendoscopic serologic test with duodenal biopsy in high-risk patients had high sensitivity and low specificity for celiac disease

Preendoscopic serologic test with duodenal biopsy in high-risk patients had high sensitivity and low specificity for celiac disease

Increasing numbers at a specialist coeliac clinic: Contribution of serological testing in primary care

Background Serological testing, using IgA class endomysial and tissue transglutaminase antibodies has high sensitivity and specificity for coeliac disease and allows case finding by clinicians other than gastroenterologists. We reviewed new coeliac patients seen over a 9-year period to determine how the availability of serology, particularly to primary care physicians, has changed rates and sources of diagnosis. Methods Files of patients attending a specialist coeliac clinic who were diagnosed from 1996 through 2004 were reviewed. Patients with villous atrophy consistent with gluten sensitive enteropathy (Marsh III) on duodenal biopsy were selected. Data analysed included clinical characteristics, endomysial and tissue transglutaminase antibodies status and source of request for serology. Results Over the study period 347 new coeliac patients, comprising adults and children aged 10 years and over, were identified, of whom 163 (47%) were identified by serological testing in primary care, 152 (44%) at the hospital gastroenterology department and 32 (9%) by other physicians in secondary care. Over three consecutive 3-year periods, the percentage of patients identified in primary care rose from 28% through 47% to 60%, with a rise in total numbers diagnosed from 93 through 118 to 136. There was no change in patient clinical characteristics over the study period. Though tissue transglutaminase antibodies were less sensitive than endomysial antibodies, combined testing obtained a sensitivity of over 90%. Patients identified in primary care were significantly younger and more likely to present with diarrhoea as a primary symptom. Conclusion Currently over half of our coeliac patients are identified by serological testing in primary care, which has resulted in an overall rise in diagnosis rates. Primary care practitioners have an important role in the diagnosis of coeliac disease, particularly of patients who present with non-gastrointestinal symptoms. The contribution of specialists other than gastroenterologists in secondary care is disappointing and may improve with directed education.

Clinical, HLA, and Small Bowel Immunohistochemical Features of Children with Positive Serum Antiendomysium Antibodies and Architecturally Normal Small Intestinal Mucosa

Antiendomysium antibodies have a high sensitivity and specificity for celiac disease. A small percentage of subjects positive for these antibodies have a small intestinal mucosa hitherto considered normal. The aim of this study was to characterize the clinical, serological, immunogenetic, and immunohistological features of these subjects. From 409 patients who were positive for celiac-related antibodies, we selected 24 (5.9%) patients who had an architecturally normal small intestinal mucosa. One hundred age-matched celiac patients with a "flat" small intestinal mucosa, and 50 age-matched nonceliac children were also studied. The number of CD3+ and gammadelta+ intraepithelial lymphocytes and of CD25+ lamina propria mononuclear cells, and the expression of crypt HLA-DR and lamina propria ICAM-1 were assessed. HLA haplotyping was also performed. Eleven (45.8%) of the 24 patients had a distinct infiltrative pattern, i.e., an increase in CD3+ intraepithelial lymphocytes (> 2SD of the nonceliac group), whereas 17 (70.8%) had a higher density of intraepithelial gammadelta+ cells. In 17 (70.8%) patients, the number of lamina propria CD25+ cells was increased and/or the expression of ICAM-1 and crypt HLA-DR was enhanced. All 24 patients carried the celiac disease-associated HLA haplotypes. Two of the six patients who remained on a normal diet and underwent a second jejunal biopsy developed villous atrophy. Most of the patients with serum antiendomysium antibodies and normal jejunal histology showed immunohistochemical signs of immune activation in the epithelium, lamina propria, and crypts. We recommend that such patients be monitored to assess their progress and to determine whether they need a gluten-free diet.

Sensitivity of serum tissue transglutaminase antibodies for endomysial antibody positive and negative coeliac disease.

Serum antibodies to tissue transglutaminase (tTGA) are reported to have high sensitivity and specificity for coeliac disease and to correlate closely with endomysial antibodies (EmA). We assessed their performance in a coeliac population with a high proportion of EmA-negative patients, who have been under-represented in previous studies. We used a commercial ELISA kit to test for IgA class tTGA in sera from a population of 73 untreated coeliac patients with normal serum IgA and a high percentage (19%) EmA-negative, taking 58 patients with normal duodenal biopsies as controls. EmA was measured using indirect immunofluorescence. Forty-six (63%) patients with villous atrophy (VA) had both tTGA and EmA. However, when considered separately, sensitivities of tTGA and EmA for VA were similar (75% versus 81%) and both had high specificity (98% versus 97%). As 9 patients were tTGA-positive only and 13 had EmA only, selection of patients for biopsy on the presence of either antibody would have had a sensitivity of 93% (68 of 73), with 5 (7%) patients seronegative for both. Although the ELISA tTGA assay is more convenient than EmA testing, it offers no advantages in sensitivity or specificity if used in isolation. However, incomplete concordance between EmA and tTGA positivity means that combination screening with both assays offers higher sensitivity, as almost a third of patients have only one antibody. As some coeliac patients with normal serum IgA are negative for both antibodies, biopsies should still be performed in seronegative individuals deemed at high risk for coeliac disease.

Sensitivity of Serum Tissue Transglutaminase Antibodies for Endomysial Antibody Positive and Negative Coeliac Disease

Background: Serum antibodies to tissue transglutaminase (tTGA) are reported to have high sensitivity and specificity for coeliac disease and to correlate closely with endomysial antibodies (EmA). We assessed their performance in a coeliac population with a high proportion of EmA-negative patients, who have been under-represented in previous studies. Methods: We used a commercial ELISA kit to test for IgA class tTGA in sera from a population of 73 untreated coeliac patients with normal serum IgA and a high percentage (19%) EmA-negative, taking 58 patients with normal duodenal biopsies as controls. EmA was measured using indirect immunofluorescence. Results: Forty-six (63%) patients with villous atrophy (VA) had both tTGA and EmA. However, when considered separately, sensitivities of tTGA and EmA for VA were similar (75% versus 81%) and both had high specificity (98% versus 97%). As 9 patients were tTGA-positive only and 13 had EmA only, selection of patients for biopsy on the presence of either antibody would have had a sensitivity of 93% (68 of 73), with 5 (7%) patients seronegative for both. Conclusion: Although the ELISA tTGA assay is more convenient than EmA testing, it offers no advantages in sensitivity or specificity if used in isolation. However, incomplete concordance between EmA and tTGA positivity means that combination screening with both assays offers higher sensitivity, as almost a third of patients have only one antibody. As some coeliac patients with normal serum IgA are negative for both antibodies, biopsies should still be performed in seronegative individuals deemed at high risk for coeliac disease.

Association between primary biliary cirrhosis and coeliac disease

Editor,—We were interested to read the paper by Kingham and Parker ( Gut 1998; 42 :120–2) as we have recently reported a study exploring the association between primary biliary cirrhosis (PBC) and coeliac disease.1 We tested serum samples from 57 patients with biopsy proved PBC for IgA class endomysial antibody. Six (11%) had endomysial antibody though only four agreed to undergo small bowel biopsy, which confirmed coeliac disease in all cases. As we have found endomysial antibody to have 100% specificity for coeliac disease,2 11% is likely to be the true prevalence of coeliac disease among our patients with PBC, which is over 15 times that of the general population in Northern Ireland.3 None of the four patients with biopsy proved coeliac disease showed improvement in liver biochemistry after exclusion of dietary gluten. Our experience of screening patients with coeliac disease for PBC was less productive.4 Of the 129 patients with coeliac disease screened prospectively for liver disease at the time …

Identification of Coeliac Disease in Primary Care

Background: Coeliac disease is common yet often undiagnosed because symptoms may be trivial, non-specific, or non-gastrointestinal, or because of lack of clinician awareness. Serum IgA-class endomysial antibodies (EmA) have high specificity for coeliac disease and may facilitate case-finding by clinicians other than gastroenterologists. We assessed the appropriateness and diagnostic yield of of requests for EmA by primary care general practitioners in a defined geographic area of Northern Ireland. Methods: We identified patients who had EmA examination requests by their general practitioners during 1994-1996. Individual patient questionnaires were posted to the general practitioners concerned, seeking information on indications for testing, management after the result, and final diagnosis. We compared new patient diagnosis rates in two catchment areas, one served by a large district general hospital with, and the other by smaller hospitals without, a medical gastroenterology facility. Results: A total of 239 patients had coeliac profile testing by 69 of 177 general practitioners in the area. Data were available for 181 patients not previously known to have coeliac disease, of whom 20 (11%) had EmA. All EmA-positive patients were referred to hospital, where 19 underwent small-bowel biopsy, which confirmed coeliac disease in all 19. Only 7 (35%) of the 20 had diarrhoea, and there was no significant difference in EmA prevalence among patients tested with and without diarrhoea. Although the mean number of new patients (per 100,000 population annually) diagnosed by biopsy was 11 at the large hospital compared with 5 elsewhere, the numbers identified by EmA in general practice for the 2 catchment areas were similar (2 and 3, respectively). Conclusion: General practitioners have an important role in the identification of patients with coeliac disease, particularly where there is no local medical gastroenterology facility, and this is facilitated by EmA testing.

Screening for coeliac disease as a possible maternal risk factor for neural tube defect

Coeliac disease is an important cause of malabsorption, particularly of folic acid, in adults. We investigated the possibility that it might be a maternal risk factor for neural tube defect (NTD)-associated pregnancy by screening affected mothers using serum endomysial antibody (EmA) which has high sensitivity and specificity for coeliac disease. One (1.6%) of 60 patients was EmA positive and had a diagnosis of coeliac disease confirmed by the finding of villous atrophy on jejunal biopsy. In conclusion, the majority of NTD-associated pregnancies are not associated with maternal coeliac disease and our study is additional evidence that abnormalities of folic acid metabolism rather than absorption are the most important risk factors for NTD. Further studies are needed to determine whether the coeliac disease prevalence among women with NTD-affected pregnancy is higher than that of the general population.