In recent years, knowledge about coeliac disease (CD) has improved significantly, and we now have a better understanding of the diagnosis and pathogenesis of the disease. In this issue of the Journal Chin and colleagues report the largest community study of CD undertaken in Australia.1 The study found a prevalence of CD of between 0.56% and 0.96%,1 similar to prevalences found in European population studies. A recent population-based serological study (without biopsy) in the United States found a prevalence of 0.95%.2

The screening strategy used by Chin and colleagues involved IgA and IgG anti-tissue transglutaminase (anti-tTG) antibody assays, HLA-DQ2 and HLA-DQ8 haplotyping, and, where appropriate, gastroscopy and duodenal biopsy.1 We believe that the data do not justify population-based screening for CD in Australia, but the diagnostic approach developed by Chin et al is appropriate for diagnosing patients in whom CD is suspected.

Genetic and environmental factors are important in the genesis of the disease. The role of the HLA-DQ2 and -DQ8 haplotypes is yet to be fully understood. One or other haplotype is present in nearly all CD patients, yet they are also present in 20%–40% of subjects without CD. The “gold standard” for diagnosis has long been histological findings from a duodenal biopsy, despite the discordance between clinical symptoms and these findings.

CD is caused by an immune response to antigens in gluten proteins. Wheat, barley and rye, but not corn or rice, contain gluten proteins. Ingested gluten is partially digested to peptides, some of which are absorbed into the lamina propria of the small intestine. The enzyme, tissue transglutaminase, deamidates certain glutamine residues in the peptides to glutamic acid. In patients with CD, this results in enhanced binding to HLA-DQ2 or -DQ8 cells. Within the lamina propria, T cell recognition of the amino acid sequences presented by the DQ2 or DQ8 cells produces a series of inflammatory changes, with the release of cytokines and the activation of lymphocytes. This leads to the characteristic histological findings in the proximal duodenum — lymphocytic infiltration, villous damage or loss, and crypt hyperplasia.3 Increases in transglutaminases in the lamina propria produce several effects: they catalyse the crosslinking of gluten peptide residues to lysine residues in various local proteins, including in transglutaminase itself, creating an immunogenic gluten–peptide–protein complex. This becomes an autoantigen, producing the characteristic IgA/IgG anti-tTG antibody of CD, which is best detected by an enzyme-linked immunosorbent assay.

The mainstay of diagnosis of CD remains the anti-tTG assay, followed by duodenal biopsy, with the patient on a gluten-containing diet (equivalent to four slices of wheat bread a day) for several weeks. It is important to recognise that false-negative test results do occur, an underappreciated cause being IgA deficiency, which occurs in one in 40 people and can be identified using a combined IgG/IgA anti-tTG assay. Recent evidence suggests that the IgA/IgG anti-tTG antibody test has superior performance (sensitivity of about 90%, specificity of about 80%) to the anti-endomysial antibody (EMA) test, is less expensive, and overcomes the potential problem of IgA deficiency.4 If doubt persists, HLA haplotyping is useful, and a negative test for both DQ2 and DQ8 effectively excludes the diagnosis.5

Several factors should raise suspicion of the presence of CD and prompt testing:

• first-degree relatives of CD patients;

• adult type 1 diabetes mellitus;

• osteoporosis;

• ill-defined abdominal symptoms (eg, irritable bowel syndrome);

• iron or other nutritional deficiency;

• unexplained transaminase elevations; or

• Down syndrome.

In patients in whom testing points to CD, the benefits of a gluten-free diet should be considered. Given that a gluten-free diet is arduous, we need to be assured that the risk–benefit ratio is appropriate. The benefits in those with florid symptoms are life-transforming (“Doctor, I never knew what it was like to be well before the diet”), but for the symptomless patient the gains in quality or quantity of life are less clear.2 Recent studies show a mild increase in risk of death from malignancy, which appears to diminish with time from diagnosis. Future research needs to quantify the benefits, if any, of lifelong treatment of people with asymptomatic and currently undiagnosed CD.

What, then, is the role of screening for CD? To be justified, population screening must be effective, acceptable and cost-effective, and these conditions are not met for CD.6

Focused screening is preferable, as shown by a number of primary care studies. A study from nine surgeries in central England screened 1000 sequential patients with an anti-EMA test and found 30 patients in whom CD was confirmed by small-bowel biopsy. Half of these 30 patients presented with anaemia.7 Another study from five general practices in Yorkshire reported positive serological results in 12 of 1200 subjects, a prevalence of 1%. In patients with irritable bowel syndrome, the figure was 3.3%; in those with iron-deficiency anaemia, 4.7%; and in those complaining of fatigue, it was 3.3%.8 In a more recent US study in primary care, all individuals with symptoms or conditions known to be associated with CD were tested: 30 of 976 patients had positive results of an anti-tTG test and 22 (2.25%) were diagnosed with CD. These studies support our recommendation of a low threshold for serological testing of patients with coeliac-associated conditions.

In summary, CD is now recognised as a common disorder, with a population prevalence of nearly one in 100 people. In most people, its manifestations are mild or non-existent. In others, it is associated with symptoms such as fatigue, iron-deficiency anaemia, and vague abdominal complaints. Rarely, CD is associated with more significant problems, such as strange neurological symptoms, hyper- or hypothyroidism and hepatic dysfunction. The most appropriate strategy for general practitioners is to have a high level of suspicion when patients present with symptoms and signs that may be attributable to CD and to test these patients.