Elsevier

The Lancet

Volume 362, Issue 9381, 2 August 2003, Pages 383-391
The Lancet

Seminar
Coeliac disease

https://doi.org/10.1016/S0140-6736(03)14027-5Get rights and content

Summary

Coeliac disease is a genetically-determined chronic inflammatory intestinal disease induced by an environmental precipitant, gluten. Patients with the disease might have mainly non-gastrointestinal symptoms, and as a result patients present to various medical practitioners. Epidemiological studies have shown that coeliac disease is very common and affects about one in 250 people. The disease is associated with an increased rate of osteoporosis, infertility, autoimmune diseases, and malignant disease, especially lymphomas. The mechanism of the intestinal immune-mediated response is not completely clear, but involves an HLA-DQ2 or HLA-DQ8 restricted T-cell immune reaction in the lamina propria as well as an immune reaction in the intestinal epithelium. An important component of the disease is the intraepithelial lymphocyte that might become clonally expanded in refractory sprue and enteropathy-associated T-cell lymphoma. Study of the mechanism of the immune response in coeliac disease could provide insight into the mechanism of inflammatory and autoimmune responses and lead to innovations in treatment.

Section snippets

Classification

The clinical classification of coeliac disease is based on the presence of gastrointestinal symptoms. Symptomatic, active, or classic coeliac disease refers to presentations with diarrhoea, with or without malabsorption; whereas in asymptomatic or silent coeliac disease, gastrointestinal symptoms are absent or not prominent even though the patient might report other non-intestinal symptoms. Latent coeliac disease is thought to be present in a person who will develop coeliac disease in the

Clinical significance

Symptomatic coeliac disease is associated with substantial morbidity caused by chronic gastrointestinal symptoms, weight loss, metabolic bone disease, anaemia, and general weakness. Implications of the disease in patients with silent coeliac disease is less clear. However, most patients with silent coeliac disease do have occult manifestations, including reduced bone density, iron or folate deficiencies,4, 5 and associated autoimmune diseases that are often of greater clinical significance than

Genetics

Coeliac disease is a multigenic disorder associated with HLA-DQ2 (DQA1*05/DQB1*02) or HLA-DQ8 (DQA1* 0301/DQB1*0302). HLA-DQ2 is expressed in more than 90% of people with coeliac disease. The expression of these HLA-DQ2 or HLA-DQ8 molecules is necessary, but not sufficient, to develop the disease. Results of studies in siblings (sib recurrence risk for coeliac disease is 10%)11 and identical twins (70% concordance)12 suggest that HLA genes are not the main causative factor in coeliac disease.

Epidemiology

On the basis of clinical frequency, coeliac disease was previously regarded as rare, occurring in 1 in 3345 people worldwide.16 However, serologic screening studies have shown the worldwide prevalence to be 1 in 266.16 Such a rate establishes coeliac disease as one of the most common genetically based diseases. Similar prevalence has been reported in most European countries, South America, and the USA.17, 18, 19 Reports from North Africa,20 Iran,21 and India22 indicate the widespread occurrence

Clinical presentation

Coeliac disease is a disorder of the proximal small intestine that can involve the entire small intestine in some individuals. This proximal location in the small intestine often results in malabsorption of iron, folic acid, calcium, and fat-soluble vitamins with resultant iron deficiency, folate deficiency, and reduced bone density. Diarrhoea, the hallmark of symptomatic coeliac disease, is mostly due to the progression of the disease into the distal small bowel.26 When only the proximal

Diagnosis

Coeliac disease can be diagnosed in the presence of characteristic changes in a small intestinal biopsy sample and improvements in clinical symptoms or histological tests on a gluten-free diet.49 Positive serological tests lend support to a diagnosis of coeliac disease, but they are not essential.

An intestinal biopsy might be done in several circumstances: if results of serological analysis are suggestive of coeliac disease; or if serological tests are negative, but clinical suspicion is high.

Serological tests

Selective IgA deficiency occurs in 1Ā·7%-2Ā·6% of patients with coeliac disease, a rate ten to 16-fold higher than that in the general population.56 Individuals with selective IgA deficiency and coeliac disease will not have IgA antibodies (endomysial antibodies, anti-tTG, and AGA [antigliadin antibodies] IgA), but usually have a raised concentration of IgG antibodies. To detect coeliac disease in selective IgA deficient individuals, total serum IgA needs to be included in the panel of tests.

Histological analysis

A major pitfall in the diagnosis of coeliac disease is in pathological interpretation of intestinal biopsies. An adequate number of biopsies needs to be taken because the disease is patchy and not all biopsy pieces will be adequately oriented for interpretation of the crypt to villous ratio. A poorly oriented biopsy, as shown by crypts cut tangentially, will falsely reduce the crypt to villous ratio.72 As a rule, at least three well oriented crypt to villous units need to be identified to

Pathogenesis and implications for innovative treatment

Coeliac disease is a T-cell mediated chronic inflammatory bowel disorder with an autoimmune component.3 Loss of tolerance to gluten is a possible cause. Although such loss of tolerance has been identified in people without the disease, as manifested by the presence of peripheral blood T cells that respond to gluten,73 the development of an anti-gluten T-cell response in the intestine is specific to people with coeliac disease.3 The reason for this occurrence is obscure; however, changes in

Poorly or non-responsive coeliac disease

Some patients have a poor clinical or histological response to a gluten-free diet. An important first step in the assessment of these patients is to confirm the diagnosis of coeliac disease by review of the original biopsy, preferably by an expert in gastrointestinal pathology72 (panel 7). However, the most common cause of a poor response is continued gluten ingestion, which might be intentional or unintentional. Therefore a consultation with an expert dietician is essential. Another reason for

Malignant disease

Malignant diseases that are more frequent in patients with coeliac disease include small bowel adenocarcinoma, oesophageal and oropharyngeal squamous carcinoma, and non-Hodgkin lymphoma.108 A gluten-free diet is thought to be protective against the development of malignant disease,109 although this might not be the case for the development of non-Hodgkin lymphoma.110

Patients with coeliac disease have a risk of small bowel adenocarcinoma that is about 80-fold greater than that of the general

Conclusion

Coeliac disease is a very common disorder and most people with the disease have the silent form. Many of these patients are identified through screening of at-risk groups. The effect of the disease on the health of those with silent coeliac disease is unclear; however, it might account for several chronic health issues including osteoporosis, infertility, autoimmune diseases, and the worsening of other serious medical conditions. Identification of genetic and environmental factors and the

Search strategy and selection criteria

We did a comprehensive MEDLINE search with the MeSH terms celiac disease and coeliac disease for articles published in English between January, 1997, and June, 2002. We also scrutinised reference lists of review articles on coeliac disease for extra articles.

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