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Limited utilization of serologic testing in patients undergoing duodenal biopsy for celiac disease
© Wiland et al.; licensee BioMed Central Ltd. 2013
Received: 27 February 2013
Accepted: 4 November 2013
Published: 9 November 2013
Clinical algorithms for the workup of celiac disease often recommend the use of serologic assays for initial screening, followed by duodenal biopsy for histologic confirmation. However, the majority of duodenal biopsies submitted to pathology for “rule out celiac” are negative. The objective of this study was to determine the underlying causes for this low diagnostic yield.
We performed a retrospective review of pathology reports from 1432 consecutive duodenal biopsies submitted for pathologic assessment to “rule out celiac” and correlated biopsy results with results for concurrent serologic testing for celiac autoantibodies.
The majority of patients had no record of serologic testing prior to biopsy, and evidence of positive serology results was found in only 5% of patients. Most duodenal biopsies were submitted as part of a multi-site GI sampling strategy that included biopsies from other locations. In this context, serologic results correlated with the likelihood of significant duodenal and non-duodenal findings, and were also helpful in evaluating patients with indeterminate duodenal histology.
The presence of a positive screening test for celiac autoantibodies does not appear to be a major driver in the decision to submit duodenal biopsies for evaluation of celiac disease, which accounts for the low incidence of findings in these samples. In patients where celiac serology testing was performed, the results were a good predictor of the likelihood of findings on biopsy.
Celiac disease is one of the most common autoimmune diseases, with an estimated prevalence of approximately 1% in various populations [1–3]. The disease is caused by an autoimmune response to gluten which leads to progressive villous atrophy in the small bowel, resulting in malabsorption. Gastrointestinal (GI) symptoms can be relatively nonspecific, such as diarrhea and abdominal pain. Systemic complications are common, and can include iron deficiency anemia and fatigue. Accurate recognition and diagnosis of celiac disease is important because implementation of a gluten-free diet can ameliorate many symptoms. If left untreated, celiac disease is associated with increased mortality in adult life from a range of causes, including autoimmune diseases and malignancy [4, 5].
For patients with an appropriate clinical history, diagnostic tools for the workup of celiac disease can be divided into three categories; serologic assays to measure celiac-associated autoantibodies, genetic assays to identify HLA-DQ2 or -DQ8, and duodenal biopsy to document the presence of villous atrophy. Although many groups have published guidelines on the diagnosis and management of celiac disease and the role of testing in this process [6, 7], surveys have found that there can be significant variation in adherence to these guidelines in different practice settings . While the exact steps of the algorithms can vary slightly depending upon the specific population being tested, most approaches recommend using serologic assays either prior to duodenal biopsy [9, 10] or concurrently with biopsy in cases with a strong clinical suspicion .
The most commonly-used serologic assays measure autoantibodies against tissue transglutaminase (tTG), deamidated gliadin (dGDN), and endomysial tissue (EMA). Antibodies against native gliadin are losing popularity because of inferior performance when compared to the newer dGDN assays [12, 13]. Although most assays measure IgA antibodies against these targets, IgG versions are also available for use in patients with IgA deficiency, a disorder commonly associated with celiac disease . The diagnostic characteristics of celiac serology tests have been well-described in many populations, and in general show analytical performance sufficient for use as a screening test [15–18]. tTG-IgA and EMA-IgA assays have shown the best diagnostic performance in most studies, with pooled sensitivities of 89- 90% and specificities of 98 – 99% in a recent systematic review of the literature . Recent studies have suggested that the use of serologic testing prior to endoscopy could potentially reduce the need for intestinal biopsy to diagnose celiac disease .
Given the high sensitivity and specificity of serologic testing, one would expect to find a fairly high diagnostic yield in duodenal biopsies for celiac disease. In a population with a disease prevalence of 1%, a test with the characteristics described above (90% Sn, 98% Sp) would have an expected positive predictive value (PPV) of roughly 47%. However, the historical experience at our institution has been that the majority of duodenal biopsies submitted for “rule out celiac” are histologically normal. In an effort to understand the causes for this discrepancy, we retrospectively examined the utilization of celiac serology in a cohort of patients who had been sent for duodenal biopsy.
An automated electronic medical record search was performed to identify any celiac serology results for the 1432 patients identified above. Serologic assays included in the search were tTG (IgA or IgG), dGDN (IgA or IgG) and EMA (IgA only). tTG IgA and IgG antibodies were measured using the respective QUANTA Lite h-tTG ELISA assays (INOVA Diagnostics, San Diego, CA), which utilize human RBC-derived tTG as the capture antigen. dGDN IgA and IgG antibodies were measured using QUANTA Lite Gliadin II ELISAs (INOVA Diagnostics, San Diego, CA), which utilize purified gliadin peptides for capture. The EMA IgA assay was performed using an indirect immunoflourescent assay (INOVA Diagnostics, San Diego, CA) with primate distal esophagus as the slide substrate. Total IgA results were also included in the routine panel to identify patients with IgA deficiency. All tests were performed in-house at the Cleveland Clinic as part of routine clinical testing in accordance with manufacturer’s recommendations. Patients with a non-negative result for any of the four assays were classified as having positive serology in the analyses that follow. tTG, dGDN, and EMA antibodies were detected in 51%, 54%, and 28% of patients with positive serologic results, respectively.
Clinical records were reviewed for the subset of 161 patients with either positive serology or biopsy results. In the cases reviewed the following information was noted: previous history of celiac disease, consumption of a gluten free diet, timing of the gluten free diet (before or after biopsy/serology), response to gluten free diet, HLA testing results, and the final clinical diagnosis. Patients were considered to have a diagnosis of celiac disease based on positive biopsy or serologic results in the context of appropriate clinical findings (such as response to gluten-free diet or prior history of CD). Finally, endoscopy reports were reviewed in the patients where serologic testing was performed to identify the indication for endoscopy.
Serologic testing in patients sent for duodenal biopsy
No serology prior to biopsy
Indication for endoscopy in patients where serologic testing was performed
Indication for endoscopy
Workup of celiac disease
Non-celiac findings in patients with multiple biopsy sites
Non-duodenal findings in patients with positive pre-biopsy serology
Duodenal findings in patients with negative pre-biopsy serology
IVA - IEL
Focal active inflammation
Mild increased lymphocytes
Evaluation for celiac disease is one of the most common reasons for duodenal biopsy. Positive findings in these biopsies are relatively uncommon, despite the widespread availability of screening assays for celiac-associated autoantibodies. The data presented here suggests that this is because the vast majority of duodenal samples being submitted for “rule out celiac” are not targeted biopsies driven by positive serologic results, but rather are part of a multi-site sampling strategy for a larger GI workup. In this type of clinical application, the diagnostic yield will necessarily be low. One limitation of the study is that because the analysis was based on EMR results, we cannot rule out the possibility that some patients were tested for celiac serology prior to referral to our system. However, these data suggest that when serologic results are available prior to biopsy, the information can be used to guide potential sampling strategies.
In patients with positive celiac serology results, non-duodenal findings were present in better than half of the patients. While many of these were non-specific changes such as chronic gastritis, significant findings such as lymphocytic gastritis and colitis were present in several patients. Because these entities are more common in patients with celiac disease , the endoscopist may wish to procure additional biopsies from sites such as stomach and colon in patients who have a positive serologic result prior to biopsy. In contrast, the value of duodenal biopsy in patients with a negative pre-biopsy serology is less clear. Histologic findings consistent with celiac disease were very uncommon in patients with negative serologies. One potential limitation of this study is that the frequency of duodenal bulb sampling was not noted, which could potentially lead to underdiagnosis of celiac disease in patients who were not adequately sampled. In the four patients where villous atrophy was observed despite a negative pre-biopsy serology, two were known CD patients, while a third patient had collagenous sprue, a variant of duodenal disease not associated with positive serology . The majority of duodenal findings in this cohort were non-specific duodenitis or IVA-IEL. Based on chart review, no patients with IVA-IEL and negative serology were ultimately determined to have celiac disease. This suggests that in the setting of negative serologic studies, duodenal biopsies rarely provide clinically useful information that support the diagnosis of celiac disease.
The decision to pursue a duodenal biopsy on a patient involves both clinical and serological factors, and the presence of high risk symptoms such as anemia or diarrhea is sufficient cause for biopsy in many published recommendations for the workup of celiac disease . In addition, some authors have advocated that duodenal biopsy should routinely be performed in patients undergoing endoscopy for GERD . However, in lower-risk patients the use of pre-endoscopy serology has been advocated as a tool that could optimize the decision to biopsy without reducing clinical sensitivity . The data shown here support this contention, but suggest that this approach has not been widely adopted when deciding to pursue duodenal biopsy. In patients where serologic data is available, the results can help in the selection of GI locations to include in a multi-site biopsy strategy. The expanded use of serology to screen patients sent for endoscopy could potentially reduce the operational expenses associated with processing and evaluating large numbers of negative biopsies, resulting in more cost-effective treatment of these patients.
Support for EMR queries and manuscript preparation was provided from departmental resources of the Robert Tomsich Pathology and Laboratory Medicine Institute. No external funding was utilized for this study.
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