Advances in the diagnosis of coeliac disease
(November 2007)
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Advances in Diagnosis of Coeliac Disease.pdf)
Coeliac Disease (CD) is a gluten-triggered autoimmune disease which often involves the bowel (causing diarrhoea, abdominal pain, and malabsorption), but may affect the skin or any other organ. In genetically-predisposed individuals, it is believed that the ingestion of gliadin (present in barley, rye, and wheat) provokes an autoimmune attack focused upon the gut lining after it has been modified by the enzyme tissue transglutaminase (TTG). Both T-cell-mediated and antibody-driven mechanisms of tissue damage occur.
Serological testing approaches looking for antibodies associated with coeliac disease have been simplified based upon recent studies. Dual-isotype (IgA + IgG) testing for antibodies to transglutaminase (TTG) offers high sensitivity (95%) and specificity (up to 99%) for CD diagnosis compared with the gold standard of characteristic duodenal mucosal biopsy changes. For this reason, gliadin antibody testing is no longer recommended for routine coeliac screening.
Abnormal duodenal histology that resolves after gluten avoidance remains the gold standard for classical coeliac disease. Elevated TTG antibodies may be relevant in patients with a normal biopsy and extra-intestinal gluten-sensitive states, such as the itchy blistering rash of dermatitis herpetiformis (DH). Table 1 lists six explanations for discrepancies between serological (TTG antibody) and histological (duodenal biopsy) results, all but one of which reflect relevant serological responses to gluten-sensitive conditions. This consideration emphasises the need for appropriate interpretation of laboratory test results in the context of the clinical assessment.
Table 1: Six Causes of Serological - Histological Discrepancy in CD |
- Self-imposed dietary restriction leading up to time of biopsy (TTG results are falsely negative in the absence of gluten intake)
- Management of associated immune conditions (eg corticosteroids can normalise gut architecture)
- Tissue analysis problems (sampling issues; subtle intra-epithelial lymphocytosis)
- Extra-intestinal CD (many dermatitis herpetiformis patients have "normal" / subtly abnormal small bowel biopsy)
- "Pre-Disease" (Latent CD) - not yet evident at gut biopsy level, but will evolve into CD with time
- True "false-positive" results (unlikely if result > 2 S.D. above mean (> 50 U/L))
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Diagnostic Advance: Coeliac HLA Genotyping
HLA-DQ2 & DQ8 allele expression is a recognised predisposing factor for development of both CD and Type I diabetes, with the presence of the characteristic genotype being necessary but not sufficient for coeliac disease expression. These particular alleles are expressed in 20% of the population, but only 1:20 (1% in total) ever develop CD, implying the presence of other genetic and environmental modulators. For this reason, a positive result on Coeliac HLA Genotyping is diagnostically quite unhelpful, and the test is not recommended for screening purposes. In contrast, however, a negative result on Coeliac HLA genotyping is highly useful, as it reduces the likelihood of CD to <1%.
In addition to the previously mentioned causes of sero-histological discrepancy, assessment of Coeliac HLA Genotype may be of use in a range of other clinical contexts (Table 2).
Table 2: Settings Where Coeliac HLA Genotyping May Be Useful |
- Clarifying ambiguous results (sero-histological discrepancy [Table 1])
- Where gluten intake or challenge is not possible or desirable
- In certain paediatric populations (endoscopy requires anaesthetic; serology falsely negative below 2 years of age)
- Where concurrent immunomodulation may “normalise” biopsies
- Where need for anticoagulation contraindicates biopsy
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Summary: Approach to Coeliac Disease Diagnosis
Coeliac HLA Genotype testing is not a good screening test for CD
Dual-isotype TTG testing as offered through HAPS displays high sensitivity and specificity for diagnosis of CD where it is clinically suspected, but clinical & histological (gut or skin) parameters remain the final arbiters
Anti-gliadin testing is no longer recommended for routine coeliac screening
Anti-endomysial antibody testing is no longer recommended for routine coeliac screening
TTG levels correlate with gluten intake, and can be used as a guide to assessment of compliance with a gluten-free diet
In contrast, Coeliac HLA Genotyping displays a high negative predictive value (hence substantially lowering likelihood of CD), and should therefore be considered in any of the settings shown in Table 2.
References
1. Reeves, Glenn E.M. et al. Diagnostic accuracy of coeliac serological tests: a prospective study. European Journal of Gastroenterology & Hepatology.2006; 18(5):493-501
2. Hyperlink to previous update on TTG antibodies [http://10.18.0.121/Cold_Fusion_Apps/internet_site/Haps/edrsrch/edindex.htm]
3. Martini S et al Comparative Evaluation of Serologic Tests for Coeliac Disease Diagnosis and Follow-Up. Clinical Chemistry. 2002; 48:960-963
4. Margaritte-Jeannin P. Tissue Antigens 2004; 63:562-567
Costs of testing
Testing for coeliac genotyping will be covered by the Medicare Benefits Schedule (Item 71151), for Medicare Eligible patients.
Frequency of testing
Testing for coeliac genotyping will be performed at a frequency of 3-4 weeks.
Sample required
A dedicated EDTA sample (2ml) is required for coeliac genotyping (room temperature).
Author
This information sheet was written by Dr Glenn Reeves. The Immunology Department of HAPS can be contacted by telephone (49214018) or facsimile (49214023).
Coeliac Testing Algorithm
