Clinical utility of serologic testing for celiac disease in ontario: an evidence-based analysis

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.

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.

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.

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.

ADULTS OR MIXED POPULATION: 1 to 17/100,000/year

2 to 51/100,000/yearIn 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.

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.

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.

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?

A literature search was performed on November 13(th), 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 1(st) 2003 and November 13(th) 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. Inclusion Criteria Inclusion CriteriaExclusion CriteriaStudies 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.

The population consisted of adults and children with untreated, undiagnosed celiac disease with symptoms consistent with the disease.

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 studiesBoth IgA and IgG antibodies were evaluated for the serologic tests listed above.

SensitivitySpecificityPositive and negative likelihood ratiosDiagnostic 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.

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.

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. (ABSTRACT TRUNCATED)