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Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease

Muhammed Hadithi, MD; B. Mary E. von Blomberg, PhD; J. Bart A. Crusius, PhD; Elisabeth Bloemena, MD, PhD; Pieter J. Kostense, PhD; Jos W.R. Meijer, MD, PhD; Chris J.J. Mulder, MD, PhD; Coen D.A. Stehouwer, MD, PhD; and Amado S. Peña, MD, PhD
[+] Article and Author Information

From Het Groene Hart Ziekenhuis, Gouda; VU University Medical Center, Amsterdam; Rijnstate Hospital, Arnhem; and University Hospital Maastricht, Maastricht, the Netherlands.


Acknowledgment: The authors thank Chad M. Gundy, PhD, Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, for his useful advice and comments.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Muhammed Hadithi, MD, Department of Gastroenterology, Het Groene Hart Ziekenhuis, PO Box 1098, 2800 BB Gouda, the Netherlands; e-mail, muhammed.hadithi@ghz.nl.

Current Author Addresses: Dr. Hadithi: Department of Gastroenterology, Het Groene Hart Ziekenhuis, PO Box 1098, 2800 BB Gouda, the Netherlands.

Dr. von Blomberg: Medical Immunology, Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.

Drs. Crusius and Peña: Laboratory of Immunogenetics, Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.

Dr. Bloemena: Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.

Dr. Kostense: Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.

Dr. Meijer: Department of Pathology, Rijnstate Hospital, PO Box 9555, 6800 TA Arnhem, the Netherlands.

Dr. Mulder: Department of Gastroenterology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands.

Dr. Stehouwer: Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands.

Author Contributions: Conception and design: M. Hadithi, C.D.A. Stehouwer, A.S. Peña.

Analysis and interpretation of the data: M. Hadithi, P.J. Kostense, J.W.R. Meijer.

Drafting of the article: M. Hadithi, C.D.A. Stehouwer.

Critical revision of the article for important intellectual content: M. Hadithi, B.M.E. von Blomberg, J.B.A. Crusius, C.D.A. Stehouwer, A.S. Peña.

Final approval of the article: M. Hadithi, C.D.A. Stehouwer, A.S. Peña.

Provision of study materials or patients: M. Hadithi, B.M.E. von Blomberg, J.B.A. Crusius, E. Bloemena, J.W.R. Meijer, C.J.J. Mulder, C.D.A. Stehouwer.

Statistical expertise: P.J. Kostense.

Administrative, technical, or logistic support: M. Hadithi.

Collection and assembly of data: M. Hadithi.


Ann Intern Med. 2007;147(5):294-302. doi:10.7326/0003-4819-147-5-200709040-00003
Text Size: A A A

Background: Estimates of the diagnostic performance of serologic testing and HLA-DQ typing for detecting celiac disease have mainly come from case–control studies.

Objective: To define the performance of serologic testing and HLA-DQ typing prospectively.

Design: Prospective cohort study.

Setting: University hospital.

Patients: Patients referred for small-bowel biopsy for the diagnosis of celiac disease.

Interventions: Celiac serologic testing (antigliadin antibodies [AGA], antitransglutaminase antibodies [TGA], and antiendomysium antibodies [EMA]) and HLA-DQ typing.

Measurements: Diagnostic performance of serologic testing and HLA-DQ typing compared with a reference standard of abnormal histologic findings and clinical resolution after a gluten-free diet.

Results: Sixteen of 463 participants had celiac disease (prevalence, 3.46% [95% CI, 1.99% to 5.55%]). A positive result on both TGA and EMA testing had a sensitivity of 81% (CI, 54% to 95.9%), specificity of 99.3% (CI, 98.0% to 99.9%), and negative predictive value of 99.3% (CI, 98.0% to 99.9%). Testing positive for either HLA-DQ type maximized sensitivity (100% [CI, 79% to 100%]) and negative predictive value (100% [CI, 98.6% to 100%]), whereas testing negative for both minimized the negative likelihood ratio (0.00 [CI, 0.00 to 0.40]) and posttest probability (0% [CI, 0% to 1.4%]). The addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, did not change test performance compared with either testing strategy alone.

Limitation: Few cases of celiac disease precluded meaningful comparisons of testing strategies.

Conclusions: In a patient population referred for symptoms and signs of celiac disease with a prevalence of celiac disease of 3.46%, TGA and EMA testing were the most sensitive serum antibody tests and a negative HLA-DQ type excluded the diagnosis. However, the addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, provided the same measures of test performance as either testing strategy alone.

Figures

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Appendix Figure 1. Slides with hematoxylin–eosin staining (for assessment of villous [crypt] anatomy) appear on the left; those with immunofluorescence-labeled, monoclonal anti-CD3 immunohistologic staining (for assessment of density of intraepithelial lymphocytes) appear on the right. Normal small-bowel mucosa is characterized by normal villous architecture, villous–crypt ratio of 4:1, and intraepithelial lymphocyte count <30 cells per 100 enterocytes. A Marsh I lesion is characterized by intraepithelial lymphocytosis, defined as intraepithelial lymphocyte count >30 cells per 100 enterocytes in mucosa whose architecture appears normal. A Marsh II lesion is characterized by intraepithelial lymphocytosis accompanied by crypt hyperplasia (elongation and branching of crypts).
Small-bowel histologic findings (Marsh 0 to II).A.B.C.
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Appendix Figure 2. Slides with hematoxylin–eosin staining (for assessment of villous [crypt] anatomy) appear on the left; those with immunofluorescence-labeled, monoclonal anti-CD3 immunohistologic staining (for assessment of density of intraepithelial lymphocytes) appear on the right. Marsh IIIa (partial villous atrophy) is a more severe stage that is characterized by intraepithelial lymphocytosis (defined as intraepithelial lymphocyte count >30 cells per 100 enterocytes in mucosa whose architecture appears normal), crypt hyperplasia, and a villous–crypt ratio <1:1. A Marsh IIIb lesion (subtotal villous atrophy) is characterized by atrophic but still recognizable villi. When villi are absent or rudimentary, the lesion is described as Marsh IIIc, or total villous atrophy.
Small-bowel histologic findings (Marsh IIIa to IIIc).A.B.C.
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Figure. NSAID = nonsteroidal anti-inflammatory drug. *Tests were positive for IgG antigliadin antibodies (AGA) in 4 patients, AGA-IgA in 8 patients, and guinea pig–IgA tissue antitransglutaminase (TGA) and antiendomysium antibodies (EMA) in 13 patients. †Tests were positive for AGA-IgG in 1 patient, tissue TGA in 1 patient, and EMA in 2 patients. ‡Tests were positive for AGA-IgG in 5 patients, AGA-IgA in 8 patients, tissue TGA in 3 patients, and EMA in 2 patients. §A gluten-free diet was prescribed to 2 seropositive patients at their request despite normal small-bowel histologic findings. ||One patient could not be reached for a follow-up small-bowel biopsy.
Study flow diagram.
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Comments

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The Confusing Clinical Diagnosis of Celiac Disease
Posted on September 13, 2007
Daniel G. Arkfeld
USC Keck School of Medicine
Conflict of Interest: None Declared

It is with great interest that I read the article entitled "Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease" by Hadithi et al. As a university based rheumatologist who sees many patients where celiac disease enters the differential diagnosis, I appreciated the effort to delineate the sensitivity and specificity of antibody testing, HLA typing, and small bowel biopsy. It is surprising to see the very low number of patients referred for small bowel biopsy who actually had celiac disease. Many fibromyalgia and irritable bowel patients are worried about celiac disease which may relate to access to clinical information via the internet, support groups as well as other sources. I often check for celiac disease but rarely find it, much like the data presented in this paper. Elimination of gluten in diets can be difficult for patients and they always think that they have not done this accurately. This is an area where HLA typing can be essential to "rule out" sprue in a patient without celiac antibodies, especially those with irritable bowel symptomatolgy.

On the other hand, I did recently see a patient with antibodies to sprue who did not improve despite aggressive dietary change. It turned out that he was eating sushi regularly with soy sauce which is high in gluten content. With restriction of soy sauce, he is now normal from a GI perspective. After reviewing this article, it would have been helpful to do HLA typing in his case. In summary, I feel that the data presented will help me clinically assess patients with GI complaints.

Conflict of Interest:

None declared

Re: The Confusing Clinical Diagnosis of Celiac Disease
Posted on December 7, 2007
Amado Salvador Peña
VUmc
Conflict of Interest: None Declared

I have read with interest the comments made by Dr Daniel G. Arkfeld. In particular the application of HLA-DQ typing to clinical practice. I like to stress another valuable addition of HLA-DQ typing in patients who have been following a gluten-free diet for years and then decide to eat normally or patients in whom for another reason have been typed and found to be negative for HLA-DQ2 and/or HLA-DQ8. I have observed a nurse and a teacher who after following the diet for 15 and 12 years respectively were found to be not carriers of these HLA-DQ specific alleles associated with celiac disease. I let them continue with the new normal diet and followed the evolution with specific serological tests (anti-endomysium antibodies, at the time human tissue transgutaminase test was not available) and after some years repeated the duodenal biopsy. They proved not to have celiac disease. The original abnormal intestinal biopsy had obviously a different etiology. Also HLA-DQ typing can be particularly important in patients who already have started a gluten-free diet without confirmation of an abnormal small intestinal biopsy. This will help to confirm or exclude the diagnosis. This is important because celiac disease patients should follow the gluten -free diet for life (so long as no other proven therapies are available) to avoid the risk of the development of malignancy later in their lives. In practice to follow a strict gluten-free diet is not only difficult but it requires discipline and constant vigilance for the patients.

Conflict of Interest:

None declared

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Summary for Patients

Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease

The summary below is from the full report titled “Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease.” It is in the 4 September 2007 issue of Annals of Internal Medicine (volume 147, pages 294-302). The authors are M. Hadithi, B.M.E. von Blomberg, J.B.A. Crusius, E. Bloemena, P.J. Kostense, J.W.R. Meijer, C.J.J. Mulder, C.D.A. Stehouwer, and A.S. Peña.

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