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Coeliac Disease and Gluten Sensitivity Syndrome

(July 2002)

(Download  Coeliac Disease and Gluten Sensitivity_Syndrome.pdf)

Coeliac disease (CD) is an inflammatory disorder of the small intestine induced by chemicals called 'prolamines' (proline-rich amines) that are found in the cereals wheat, barley and rye. Typically, CD presents with malabsorption characterised by weight loss, abdominal distension, diarrhoea and steatorrhoea, but the breadth of pathology can extend beyond the gastrointestinal tract. Most notably causing the blistering pruritic skin rash of dermatitis herpetiformis and the neurological complication of gluten ataxia.

Histology of jejunal mucosa demonstrating villous atrophy establishes the diagnosis of CD, and may be used for assessment following dietary intervention. Serological tests have enabled a more selective use of endoscopic procedures in patients with a high probability of disease, and provide an alternative method for monitoring dietary intervention and compliance.

The Role of Serological Screening must be Re-Evaluated

The diagnostic criteria for CD remain inadequate to encompass the whole range of presentations of gluten sensitivity. The diagnostic "gold standard" for CD requires biopsy evidence of small bowel villous atrophy that normalises with dietary restriction and deteriorates upon rechallenge. This allows most patients with symptomatic gut disease to be diagnosed, but excludes a significant number of people with 'latent' coeliac disease, dermatitis herpetiformis, gluten-induced ataxia, and other presentations (Table 1).

In most of the studies of coeliac serology to date, positive antibody results in the absence of demonstrable bowel pathology have been labelled as 'false positives', thus reducing the diagnostic specificity of serology. It is quite possible that many of these patients with 'normal' small bowel biopsies but high titre antibodies to endomysial, gliadin or transglutaminase antigens could be included in the category of gluten sensitivity syndrome if other clinical features are evident. Particularly if the positive serology occurs in the setting of appropriate HLA haplotypes, family history, or other autoimmune conditions such as IDDM or autoimmune thyroiditis.

Important Messages for Serological Screening for Coeliac Disease

• No serological screen replaces small intestinal biopsy for diagnosing intestinal gluten sensitivity or skin biopsy for diagnosing dermatitis herpetiformis (DH) and other forms of skin-based gluten sensitivity.
• Testing with IgA transglutaminase antibody (A-TGA) is diagnostically equivalent to endomysial antibody testing for detecting intestinal gluten sensitivity states, as both of these assays target the same antigen. IgA endomysial antibodies (A-EMA) are therefore being discontinued by HAPS Immunology, and will be replaced by A-TGA.
• IgA-endomysial antibodies (A-EMA) and IgA-TGA (A-TGA) may not be as sensitive as earlier literature suggests, missing 10-20% of gluten-sensitive individuals. The presence of normal total serum IgA levels does not guard against this diagnostic limitation of IgA-based approaches.
• No serological test is reliable in children < 2 years of age.
• A-TGA and IgA gliadin antibody (A-AGA) offer similar utility in monitory compliance with a gluten-free diet.
• False positive A-AGA, A-EMA and A-TGA are seen in individuals with organ-specific and systemic autoimmune conditions and in Down syndrome. Given the higher prevalence of CD in these individuals, positive results should be treated seriously. A lower threshold for tissue biopsy assessment should exist. Follow-up should be considered where sero-positivity persists despite initially negative histology, as latent CD may present.
• The results of serological testing do not correlate well with histological reconstitution, so there is an ongoing role for clinically determined endoscopic follow up.
• Follow-up serological testing should occur in the following situations:
• Where suspicion of CD persists despite initial negative serology, especially in individuals from at-risk populations (Table 2).
• Where initial serological screening is equivocal or discrepant.
• Where sero-positivity persists despite initial negative histology (latent CD may present).
• Where doubt exists about whether initial testing occurred in the context of self-imposed gluten restriction.

At-Risk Groups for Coeliac Disease

• IgA-deficient individuals.
• First and (possibly) second degree relatives of CD patients.
• Patients with IDDM and their first degree and (possibly) second-degree relatives.
• Patients with either Down or Turner Syndromes.
• Patients with Sjogren's syndrome and related systemic autoimmune conditions.

HAPS Immunology Recommendations

The following screening approach is recommended for coeliac disease and associated gluten sensitivity conditions:

• IgA transglutaminase antibodies (target antigen)
• Gliadin antibodies (includes assessment of IgA and IgG-based serology) *
• Total IgA (up to 10% of individuals with CD are IgA-deficient)

* Currently, HAPS Immunology is prospectively assessing the screening utility of a simplified approach using IgA-TGA plus IgG-TGA. Until sufficient data has been assessed this TGA strategy can not be recommended.

Normal Ranges

In normal individuals, transglutaminase antibodies are negative (< 20 ELISA Units) and endomysial antibodies are negative.

The reference ranges for gliadin antibodies are age-dependent (Table 3).

Specimen Collection

A 5mL clotted blood sample is required. Plasma is unsuitable. Samples may be stored and transported at 4° C for up to 48 hours.

References

1. Maki M, Collin P. Coeliac disease. Lancet 1997; 349: 1755-1759.
2. Walker-Smith JA, Guandalini S, Schmitz J et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:09-911.
3. Unsworth DJ, Brown KL. Serological screening suggest that adult coeliac disease is under diagnosed in the UK and increases the incidence by up to 12%. Gut 1994; 35:61-64
4. Bruce SE, Bjarnason I, Peters TJ. Human jejunal transglutaminase: Demonstration of activity, enzyme kinetics and substrate specificity with special relation to gliadin and coeliac disease. Clin Sci 1985; 68:573-579
5. Lundin KEA, Scott H, Hansen T, et al. Gliadin-specific, HLA-DQ (1*0501, 1*0201) restricted T cells isolated from the small intestinal mucosa of coeliac disease patients. J Exp Med 1993; 178:187-196
6. Molberg O, Kett K, Scott H et al. Gliadin specific, HLA-DQ2-restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand J Immunol 1997; 46: 103-109
7. Petterson A, Sjoberg K, Lernmark A et al. HLA genotypes in coeliac disease and in healthy individuals carrying gliadin antibodies. Eur J Gastroenterol Hepatol 1993; 5:445-450
8. Ferreira M, Davies SL, Butler M et al. Endomysial antibody: Is it the best screening test for coeliac disease? Gut 1992; 33:1633-1637
9. Dieterich W, Ethnis T, Bauer M et al. Identification of tissue transglutaminase as the autoantigen of coeliac disease. Nature Medicine 1993; 7:797-801
10. Reeves GEM, Burns C, Hall ST et al. The measurement of IgA and IgG transglutaminase antibodies in coeliac disease: A comparison with current diagnostic methods. Pathology 2000; 32:181-185

About the Authors

Dr Glenn Reeves, A/Professor Maree Gleeson and Karla Lemmert, HAPS Immunology wrote this HAPS Communique. If you have any questions regarding this topic the Immunology staff would be happy to assist you on: Telephone: (02) 49214000, Facsimile: (02) 49214400

Immunology Contacts

Glenn Reeves - Staff Specialist - 49214000

Professor Robert Clancy - Staff Specialist - 49236135

Immunology Laboratory - 49214000