Diagnostic Significance of HLA-DQ Typing in Patients With Previous Coeliac Disease Diagnosis Based on Histology Alone

A. Kipatány; L. Tóth; J. Tumpek; I. Csípö; E. Sipos; N. Woolley; J. Partanen; G. Szegedi; É. Oláh; S. Sipka; I. R. Korponay-Szab


Aliment Pharmacol Ther. 2006;24(9):1395-1402. 

In This Article

Summary and Introduction


Background: Coeliac disease is strongly associated with human leukocyte antigen (HLA)-DQ2 or DQ8 genotypes. The diagnosis is based on demonstrating crypt-hyperplastic villous atrophy, endomysial or transglutaminase antibodies and correlation of disease activity with gluten intake.
Aim: To evaluate the clinical utility of HLA-DQ typing, when coeliac disease diagnosis had previously been established solely by histology.
Methods: HLA-DQ alleles, endomysial and transglutaminase antibodies were investigated and histology slides reviewed in 70 patients diagnosed 2–25 years earlier by small-intestinal biopsy but without measuring endomysial or transglutaminase antibodies. Patients without DQ2 or DQ8 or without unequivocal villous atrophy were followed-up on free diet by using serology and biopsies.
Results: All 40 endomysial/transglutaminase antibodies positive patients carried DQ2 or DQ8, and 39 of them had severe villous atrophy. Only 56% of patients without endomysial or transglutaminase antibodies positivity had DQ2 or DQ8 (P < 0.001). Seropositivity and relapse developed in 4 of 11 DQ2 positive but in none of 15 DQ2 and DQ8 negative patients on long-term gluten exposure.
Conclusions: Coeliac disease diagnosis based solely on histology is not always reliable. HLA-DQ typing is important in identifying DQ2 and DQ8 negative subjects who need revision of their diagnosis, but it does not have additive diagnostic value if endomysial positivity is already known.


Coeliac disease is a T-cell-mediated chronic inflammatory disease of the small intestine, which occurs in 1% of the European population. In genetically susceptible persons, small bowel mucosal inflammation, crypt hyperplasia and villous atrophy develop after ingestion of gluten, present in wheat, rye and barley.[1] Active coeliac disease is characterized by disease-specific antibodies against endomysium (EMA) or tissue transglutaminase (anti-TG),[2,3] and their presence in serum[3,4] or locally in the gut[5] is of high diagnostic value. Most common symptoms are weight loss, pale offensive diarrhoea or constipation and abdominal bloating, but clinical symptoms may even be absent or only involving extraintestinal organs (e.g. osteoporosis). The intolerance towards gluten lasts life-long, but elimination of gluten from the diet results in complete remission, thus in disappearance of symptoms, antibodies and histologic abnormalities.[2,4]

Coeliac disease is a strongly inheritable disease with 10% prevalence among first-degree relatives and at least 75% concordance in monozygotic twins compared with 11% in dizygotic twins.[6] Approximately, 90–95% of patients carry the human leukocyte antigen (HLA)-DQ2 heterodimer composed of DQA1*05 and DQB1*02 molecules, either encoded in cis position together with DRB1*03 or in trans with DRB1*05/07.[7] The remaining patients usually have DR4;DQ8 haplotypes (DQA1*0301, DQB1*0302 alleles) with extremely few exceptions.[8] Patients negative for both HLA-DQ2 and −DQ8 are very unlikely to suffer from coeliac disease, because these molecules are necessary to present the antigens to T cells.[7,9] Gluten peptides are substrates for tissue transglutaminase enzyme that transforms glutamine residues to negatively charged glutamic acid residues by deamination. With these negative charges, DQ2 and DQ8 molecules (which have positively charged binding pockets) will be able to bind and present them to CD4+ T cells. In Hungary, the first HLA study in patients with gluten enteropathy was performed by Kárpáti et al. in 1985,[10] and subsequent reports further confirmed the strong association of coeliac disease with DQ2 and DQ8 molecules both in Hungarian children and adults.[11,12]

The presence of HLA-DQ2 or DQ8 is necessary but not sufficient for the development of coeliac disease, because they also occur in 20–30% of the general European population. Moreover, also non-HLA genes have an important but yet unclarified contribution in disease development.[13] However, HLA-DQ typing may have clinical relevance in estimating the risk of family members, or to evaluate the probability of coeliac disease in uncertain cases. A low prevalence of DQ2 or DQ8 was found among patients who started a gluten-free diet without a confirmatory small bowel biopsy.[14] The gold standard of coeliac disease diagnosis is today small bowel histology, but its evaluation may have several pitfalls.[15,16] Some features, such as elevated intraepithelial lymphocyte count or shortening of the villi, are non-specific changes, and also may occur in other diseases, such as nutritive allergy or postinfectious damage.[17] In this study, we investigated the value of HLA-DQ typing in cases where the diagnosis of coeliac disease was based on an earlier pathology statement but information on the presence of EMA or anti-TG was lacking.


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