Predictive Value For Celiac Disease Research Articles

A Clinician's Guide to Celiac Disease HLA Genetics.

Celiac disease is a common inflammatory disease triggered by dietary gluten in genetically susceptible individuals. The strongest and best-characterized genetic susceptibilities in celiac disease are class II human leukocyte antigen (HLA) genes known as HLA-DQ2 and DQ8. HLA genetic testing is available through a number of commercial and academic laboratories and is used in the evaluation of celiac disease and to identify at-risk family members. Importantly, HLA genetic testing has a high negative predictive value for celiac disease, but a low positive predictive value. Therefore, for a practicing clinician, it is important to understand when to order HLA genetic testing, what test to order, and how to interpret the result. This review provides a practical primer on HLA genetics in celiac disease.

In Screening for Celiac Disease, Deamidated Gliadin Rarely Predicts Disease When Tissue Transglutaminase Is Normal.

While tissue transglutaminase (tTG) antibodies are the most established serological test for celiac disease, newer deamidated gliadin peptide (DGP) screening tests are increasingly being completed. No pediatric study has systematically assessed the incidence of celiac disease in patients with an isolated positive DGP result. We sought to determine the positive predictive value of DGP serology for biopsy-confirmed celiac disease in pediatric patients with elevated DGP and normal tTG, to help guide clinicians' decision making when screening for this common condition and avoid unnecessary invasive follow-up diagnostic testing. A multicenter retrospective review of children, from birth to age 18, with isolated DGP immunoglobulin G (IgG) positive serology referred to 3 Canadian centers was completed. The positive predictive value of an isolated elevated DGP result was calculated. Forty patients with DGP positive, tTG negative serology underwent endoscopy with duodenal biopsy. Of these, only 1 patient had biopsy-confirmed celiac disease. This patient was IgA deficient. This yields a positive predictive value of 2.5% (95% confidence interval 0.1%-14.7%) for isolated DGP IgG positive serology. In isolation, DGP positive serology has a poor positive predictive value for celiac disease in children, especially in IgA sufficient individuals. Our findings suggest that DGP IgG testing should not be completed as part of the initial screening for celiac disease in the pediatric population as it does not effectively differentiate between individuals with and without the disease. Further research is needed to clarify to role of DGP IgG in children under the age of 2 and those with IgA deficiency.

Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective.

The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work-up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence-based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results.

Utility of Testing Patients, on Presentation, for Serologic Features of Celiac Disease

Celiac disease shares features of other disorders. It can be diagnosed conclusively only based on duodenal histology analysis, which is not practical for screening purposes. Serologic analysis might be used to identify candidates for biopsy analysis. We aimed to develop a simple diagnostic approach that all clinicians could follow to increase the percentage of patients accurately diagnosed with celiac disease at initial presentation. We performed a retrospective analysis of data from 752 patients (88 with celiac disease, none were IgA deficient) who attended a UK district general hospital from January 2007 through December 2008 and underwent biopsy analysis and serologic tests to measure endomyseal antibodies and IgA antibodies against tissue transglutaminase (tTG). Patients avoiding gluten in their diet were excluded. Patients were assigned to 1 of 4 groups: high-risk (based on presence of anemia, chronic diarrhea, unintentional weight loss, or dermatitis herpetiformis), low-risk (based on such factors as dyspepsia, abnormal liver function, ataxia, or chronic cough), nutrient deficiency (based on levels of iron, vitamins B12 and D, or folate), or screening (because they had type 1 diabetes or a family history of celiac disease). Patients with celiac disease were identified using the modified Marsh criteria (grades 1-3) for interpreting duodenal histology. We compared clinical category, serology profiles, and biopsy results between patients with and without celiac disease. Celiac disease was diagnosed in 64 of 565 patients in the high-risk group (11%), 14 of 156 patients in the low-risk group (9%; P = .47 compared with high-risk group), 7 of 28 patients in the nutrient-deficiency group, and 3 of 3 patients in the screening group. Among 71 patients who tested positive for both antibodies (tTG and endomyseal antibodies), the positive predictive value for celiac disease was 97%; a negative test result for tTG had a negative predictive value of 98%. Among 708 patients with normal-looking biopsy samples, only 62 had celiac disease (9%). Among 44 patients with abnormal biopsy samples, 26 had celiac disease (59%). Based on a retrospective analysis, patients with and without celiac disease cannot be distinguished based on clinical features. Patients who present with symptoms of celiac disease should be tested for tTG, to identify candidates for duodenal biopsy analysis.

A multiplex assay to rapidly exclude HLA-DQ2.5 and HLA-DQ8 expression in patients at risk for celiac disease

Celiac disease (CD) is an inflammatory disorder of the small intestine induced by gluten ingestion. CD has a strong genetic association with human leukocyte antigen (HLA)-DQ2.5 and HLA-DQ8. The absence of HLA-DQ2.5 and HLA-DQ8 has a strong negative predictive value for CD. Genetic screening of HLA-DQ2.5 and HLA-DQ8 in patients at risk is of great value. We designed, developed, and validated a multiplex assay based on multiplex ligation-dependent probe amplification (MLPA) technology, allowing the simultaneous detection of DQA1*05-DQB1*02, encoding HLA-DQ2.5, and DQA1*03-DQB1*03:02, encoding HLA-DQ8. The amplified products were separated and identified using capillary electrophoresis. When compared with a polymerase chain reaction followed by single-strand conformation polymorphism/ heteroduplex analysis, one discrepancy was found. Sequencing analysis showed that the developed MLPA assay result was correct. Furthermore, we demonstrated that the MLPA method is able to distinguish between the heterozygote and homozygote expression of HLA-DQ2.5 or HLA-DQ8. This study shows that it is possible to rapidly and accurately screen for the absence of HLA-DQ2.5 and HLA-DQ8 using MLPA, excluding patients at risk for CD for further serological or histological follow-up. In addition, MLPA might be an accurate tool to screen for other specific HLA types in the context of disease association in a diagnostic laboratory setting.

Noncoeliac enteropathy: the differential diagnosis of villous atrophy in contemporary clinical practice

Duodenal villous atrophy (DVA) is a key diagnostic finding in coeliac disease (CD). However, the differential diagnosis for this finding is broad. To identify conditions causing noncoeliac enteropathy (NCE) with villous atrophy and methods to differentiate between CD and NCE in clinical practice. Through record review we identified patients with DVA due to conditions other than CD. Patient demographics, clinical features and relevant investigations were compared with CD patients. Rates of CD misdiagnosis, and response to treatments were recorded. Thirty cases of NCE were identified with ten different aetiologies. Unspecified immune-mediated enteropathy was the most common aetiology; affecting 10 patients. Gastrointestinal symptoms were more common in NCE than those in CD patients (P < 0.01). Twenty of the 24 NCE patients tested were HLA-DQ2/DQ8 negative. Twenty-six NCE patients were negative for IgA tissue transglutaminase (tTG) (P = 0.0001). Intraepithelial lymphocytosis was absent in 10 (33.3%) patients. Twenty-one NCE patients initially misdiagnosed with CD and one with gluten intolerance were prescribed a gluten free diet (GFD). Fifteen of 22 had repeat biopsy and none showed histological improvement. Although coeliac disease is the most common cause of DVA, noncoeliac enteropathy is not rare and may easily be mistaken for coeliac disease. Noncoeliac enteropathy is suggested by a normal initial tTG (87%), lack of intraepithelial lymphocytosis on biopsy, and lack of histological response to a gluten free diet. Subjective response to gluten free diet has poor predictive value for coeliac disease. Noncoeliac enteropathy can often be confirmed by negative HLA-DQ2/DQ8 testing and targeted investigations can ascertain a definitive aetiology in most cases.

Coeliac disease: a biopsy is not always necessary for diagnosis

In view of the high diagnostic accuracy of immunoglobulin-A-tissue transglutaminase antibodies for detecting coeliac disease, we have explored whether a small bowel biopsy is always required to establish the diagnosis. To define the transglutaminase antibody level giving a positive predictive value for coeliac disease of 100% and to subsequently assess the proportion of new diagnoses of coeliac disease having such a result. The Celikey kit (Phadia GmbH, Frieburg, Germany) was used to measure transglutaminase antibody levels. All patients with transglutaminase antibody levels >30 U/mL, i.e. 10 x upper limit of normal in 2002/2003 had characteristic small bowel mucosal lesions. In a subsequent audit, 58% of 112 new diagnoses of coeliac disease in 2004/2005 had levels above this cut-off value. We have shown that a transglutaminase antibody level can be defined which gives a positive predictive value of 100% for coeliac disease. From published data, these observations can be extended to most second-generation transglutaminase antibody kits. Our data provide further evidence that diagnostic guidelines could be modified so that small bowel biopsy is no longer regarded as mandatory in patients with such high transglutaminase antibody levels. This will avoid an invasive procedure and lead to a more rapid diagnosis and earlier treatment for over half of the new patients with coeliac disease.

The diagnostic accuracy of serologic tests for celiac disease: A systematic review

Clinicians are increasingly utilizing noninvasive serologic tests for the diagnosis and screening of celiac disease (CD). The aim of this study was to conduct a systematic review of the diagnostic performance of serologic tests for the diagnosis and screening of CD. Standard systematic review methodology was used. A literature search was conducted in MEDLINE (1966 to October 2003) and EMBASE (1974 to December 2003) databases. A weighted mean of the sensitivity and specificity along with 95% confidence intervals and summary receiver operating characteristic (ROC) curves were calculated. The pooled specificity of endomyseal antibody (EMA)-monkey esophagus (ME) or EMA-human umbilical cord (HU) was close to 100% in adults and children. The pooled specificity of transglutaminase antibody (tTG)-guinea pig (GP) and tTG-human recombinant (HR) were between 95% and 99%. IgA-EMA-ME demonstrated sensitivities of 96% and 97% in children and adults, respectively. EMA-HU demonstrated a similar sensitivity of 97% in children but 90% in adults. The pooled sensitivity of tTG-GP in adults and children was 90% and 93%, respectively. The sensitivity of tTG-HR was 98% and 96%, respectively. The performance of antigliadin antibody was inferior to that of EMA and tTG. EMA and tTG offer high sensitivity and specificity. The sensitivity of these tests appears to be lower than reported when milder histologic grades are used to define CD (below 90%). If true, the nearly perfect negative predictive value of these tests would drop. The positive predictive value of these tests is likely lower than reported when the tests are applied in low-prevalence populations.

Adult Celiac Disease: Report of a Case

Adult Celiac Disease: Report of a Case

IgA antiendomysium antibodies have a high positive predictive value for celiac disease in asymptomatic patients.

Many attempts have been made to find screening tests for celiac disease to reduce the need for biopsy, or to achieve better selection criteria before intestinal biopsy. We have recently analyzed apparently healthy blood donors for antigliadin antibodies (AGA) to select subjects for further gastrointestinal investigation. A prevalence of gluten enteropathy of at least 1/256 was found in this population. The positive predictive value (+PV), however, was only 20%. In the present study we have analyzed IgA antiendomysium antibodies (IgA-EmA) to estimate the sensitivity and specificity of the test, and determine whether or not the +PV of the assay increases when screening for adult celiac disease in an asymptomatic population. We found that asymptomatic persons with celiac disease may have IgA-EmA. We found a 100% specificity of IgA-EmA in the tested population of blood donors, whereas the sensitivity was about the same as that of IgA-AGA. This result of a +PV of 100% indicates that a positive IgA-EmA could replace biopsy in diagnosing celiac disease. However, further extended studies are needed to determine whether this is applicable in other populations. To screen patients for celiac disease, we recommend the easy and cheap IgA-AGA assay as a preliminary test and the IgA-EmA to verify the diagnosis and avoid unnecessary biopsies.

Predictive value for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending for jejunal biopsy.

To investigate the extent to which the detection of antibodies to gliadin, endomysium, and jejunum predicts the eventual diagnosis of coeliac disease according to the revised ESPGAN diagnostic criteria in a group of patients in whom there is a high suspicion of coeliac disease. Clinical assessment and laboratory analysis of patients with suspected coeliac disease. Gastroenterology department of teaching hospital. 96 adults with suspected coeliac disease attending for jejunal biopsy. Diagnosis of coeliac disease with the revised criteria of the European Society of Paediatric Gastroenterology and Nutrition in patients with and without antibodies associated with coeliac disease. 28 patients had a clinical diagnosis of coeliac disease, seven of other gastrointestinal diseases, and 12 of miscellaneous diseases; 49 had no diagnosis. Gliadin IgA detected by ELISA was found in all patients with coeliac disease and none of those without, giving a sensitivity, specificity, positive and negative predictive values, and predictive efficiency of 100% for diagnosing coeliac disease within the group. Endomysial IgA was found in 25 (89%) patients with coeliac disease and jejunal IgA in 21 (75%); neither IgA was found in patients without coeliac disease. Detection of gliadin IgA by ELISA and to a lesser extent the endomysial IgA should allow better selection of patients for jejunal biopsy and thus make diagnosing coeliac disease simpler and more efficient.