Coeliac disease is a common disorder affecting the gastrointestinal tract, secondary to an immunologic reaction to gluten. At present it can only be managed by lifelong avoidance of gluten, and thus presents a challenge for patients and their health care professionals.

Epidemiology

Coeliac disease was first characterised in the late 1940s with diarrhoea and failure to thrive in young children. The wartime shortage of wheat, and adoption of a gluten-free surrogate diet, allowed their symptoms to improve. When wheat was re-introduced into their diets their condition worsened again.Initially thought to be a rare disease of children, we now recognise coeliac disease to be prevalent in adults, including the elderly. Data from the UK reveal that the most common age group diagnosed is between 30 and 45, with more people over 60 than those under 16 years (Coeliac UK: www.coeliac.co.uk).The illness occurs in people of European, Turkish, Middle Eastern, Egyptian and Indian backgrounds. It appears to be rare in sub-Saharan Africa and South-East Asia.There is debate over mass screening in populations such as in the UK and Scandinavia, where the disease incidence approaches 1%.The Gastroenterological Society of Australia (GESA) recommends screening in persons with Type 1 diabetes mellitus, Down syndrome, Turner syndrome, immunoglobulin A (IgA) deficiency, or a family history of coeliac disease, where the condition may be as common as 1 in 10.

Immunopathology

The pathologic understanding of coeliac disease has advanced considerably over the past 10 years, although our understanding is still incomplete.In some individuals, when gluten is digested the peptides cross the intestinal mucosa where they are recognised by the mucosa-associated lymphoid tissue.Those individuals with HLA-DQ2 or -DQ8 are able to process the gluten peptides, resulting in presentation of gliadin/gluten peptides on the surface of antigen-presenting cells. Over 99% of coeliac patients have HLA-DQ2 or -DQ8, and homozygotes for DQ2/8 are more likely than heterozygotes to develop the disease, and more severely.For the peptides to be presented to T cells, they must first be deamidated by a ubiquitous enzyme, tissue transglutaminase (tTG).Tissue transglutaminase alters the gluten-derived peptide so that it remains in the binding site of the HLA molecule, and allows an immune response to occur against the enterocytes that carry the HLADQ2/8-gluten peptide complex.Tissue transglutaminase is present in an active form outside cells; its usual role is to help maintain the extra-cellular matrix.Several isoenzymes of tTG exist throughout the body, tTG2 being present in the GI tract. It is the presence of IgA antibodies to this enzyme— anti-tTG2 antibodies (hereafter ‘tTG antibodies’)—that have become the gold standard serologic marker for coeliac disease. It remains uncertain why antibodies to tTG develop in coeliac patients, although research suggests that tTG can become cross-linked to the gluten peptide and cause specific tTG antibodies to develop, through a process termed ‘epitope spreading’.Tissue transglutaminase antibodies have been shown to pre-date the development of the histologic changes of coeliac disease.It is clear that antibodies to tTG are not pathogenic in most patients, as many cells in the body contain similar tTG. However, in dermatitis herpetiformis, a disease long associated with coeliac disease, these antibodies develop against tTG3 (whereas in coeliac disease they are directed against tTG2). In dermatitis herpetiformis, these tTG3 antibodies may well be pathogenic, leading to classic cutaneous lesions.

Serologic testing

IgA tTG antibodies are now considered the gold standard in the detection of coeliac disease, giving a sensitivity of around 95%, and a specificity of around 90%.IgA tTG antibodies become negative 9–12 months after the introduction of a gluten-free diet. In children less than 2 years of age, IgA production is not mature and may result in false negative IgA tTG. This is especially true for those less than one year of age.At present, all serologic diagnoses should be confirmed by histologic diagnosis, as false positives can occur. Although several studies in children have indicated that very high IgA anti-tTG results may not need to be confirmed by biopsy, Australian guidelines indicate the need for histologic confirmation.IgG tTG antibodies may also be detected in coeliac patients, though they have similar problems to IgG anti-gliadin antibodies (AGA, discussed below), with a poor sensitivity and specificity, despite initial enthusiasm for their utility.Older serologic tests for coeliac disease were based on antibodies directed against gliadin—anti-gliadin antibodies (IgA AGA and IgG AGA). Like all food antibodies, they have relatively poor sensitivity (false negatives) and particularly poor specificity (false positives), especially given that they are a group of antibodies (polyclonal), rather than being directed against a single epitope.The indication for IgA AGA is very limited and should largely be consigned to history. However, these antibodies can be used to monitor early adherence to a gluten-free diet as they become negative 6–9 months after the diet is introduced. IgG AGA, however, remains of use in IgA-deficient patients in whom IgA tTG and IgA AGA are not produced.IgG against deamidated gliadin is of use in IgA-deficient patients in whom IgA tTG and IgA AGA are not produced. This is a modified test, using a gliadin peptide (small piece of protein) that had been altered to more closely resemble the natural peptide found in wheat.IgA deficiency is defined as ‘undetectable or barely detectable’ serum IgA.IgG AGA are also of use in children less than two years of age (and especially children under one), in whom the ability to produce IgA antibodies has not fully developed.All patients with IgA deficiency in whom coeliac disease is suspected should undergo a small bowel biopsy, regardless of the IgG AGA and other testing conducted. It is suggested they be referred to a gastroenterologist, as other diseases such as chronic giardia and autoimmune enteritis may occur.One theory to explain why IgA deficiency is associated with the development of coeliac disease is that IgA is involved in the neutralisation of foreign antigens at mucosal surfaces, and these deficient individuals have greater transmucosal passage of gliadin fragments.Another type of antibody, IgA endomysial antibodies, has also been used to test for the disease in the past. These antibodies were first detected in monkey oesophagus; it is now recognised that the antigen being detected by this method was tTG.These antibodies are highly specific (~ 100%) but have a slightly lower sensitivity (~ 90%) than IgA tTG. Endomysial antibodies are sometimes used in children under two years of age.

Tissue typing

In selected cases, HLA-DQ typing may be of benefit. In patients who are predisposed to the development of coeliac disease, a negative test would essentially rule out the diagnosis. A positive result, on the other hand, would not significantly alter the chance of the person having coeliac disease.In Down syndrome and Turner syndrome patients, this would alleviate the need for life-long screening. Tissue typing may be of value in infants (less than two years), to exclude disease, as serologic markers are less reliable.HLA-DQ typing in relatives of coeliac patients may also be of use, although they are highly likely to have DQ2/8 present, whether or not they also have the disease. As DQ2 is independently associated with IgA deficiency and Type 1 diabetes, tissue typing would be less beneficial in such cases.

---

General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs.The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.