Elsevier

The Lancet

Volume 373, Issue 9673, 25 April–1 May 2009, Pages 1480-1493
The Lancet

Seminar
Coeliac disease

https://doi.org/10.1016/S0140-6736(09)60254-3Get rights and content

Summary

Coeliac disease is a chronic inflammatory disorder of the small bowel induced in genetically susceptible people by the irritant gluten and possibly other environmental cofactors. The disorder is characterised by a diverse clinical heterogeneity that ranges from asymptomatic to severely symptomatic, and it manifests with frank malabsorption, an increased morbidity attributable to the frequent association with autoimmune disorders and increased mortality resulting from the emergence of T-cell clonal proliferations that predispose the patient to enteropathy-type T-cell lymphoma. Our understanding of the molecular basis for this disorder has improved and enabled the identification of targets for new therapies, although a strict gluten-free diet remains the mainstay of safe and effective treatment. In this Seminar we critically reassess the clinical and diagnostic aspects of this disease and new perspectives in its pathogenesis and treatment.

Introduction

Coeliac disease is a chronic inflammatory disease characterised by flattened villi on the small bowel mucosa, and is induced in genetically susceptible people by the ingestion of proline-rich and glutamine-rich proteins in wheat, rye, and barley. Researchers postulate that the condition first developed after the last ice age in the fertile crescent of the Middle East with the cultivation of grains, and the first description dates from the 1st and 2nd centuries CE.1 Coeliac disease has a diverse clinical heterogeneity, and increases both morbidity and mortality. However, knowledge of many aspects of this disorder is inadequate—even in the academic specialty setting.2

Section snippets

Epidemiology

The accuracy of estimates of the true prevalence of coeliac disease has been substantially improved by the increased reliability of serological tests—namely for IgA antigliadin antibodies, initially, then for antiendomysial antibodies and IgA antihuman tissue transglutaminase (hTTG) antibodies. In large population samples, these tests enable screening for people who need a biopsy to confirm intestinal coeliac lesions. By means of this approach, the prevalence of biopsy-proven coeliac disease in

Causation

Coeliac disease develops as a consequence of the encounter between an environmental trigger and a genetically predisposed host, with the possible participation of other environmental cofactors (figure 1).

Pathophysiology

Study of the pathogenesis of coeliac disease has focused on the mechanisms by which gluten peptides, after crossing the epithelium into the lamina propria, are deamidated by tissue transglutaminase and then presented by DQ2+ or DQ8+ antigen-presenting cells to pathogenic CD4+ T cells. Once activated, the CD4+ T cells drive a T-helper-cell type 1 response that leads to the development of coeliac lesions—namely intraepithelial and lamina propria infiltration of inflammatory cells, crypt

Mode of presentation

Until 30 years ago, the use of intestinal biopsy was reserved for patients with symptoms of overt malabsorption and, consequently, the prevalence of malabsorption among patients with coeliac disease was very high. At the beginning of the 1980s, awareness of the disease improved and a lowered threshold for its investigation led us to acknowledge the more subtle and variable clinical expression of the condition. At the end of the 1980s—after the advent of serology—the number of patients with

Case finding

The burden of undetected disease is very high: a cautious prevalence estimate of 0·5% equates to around 2·5 million patients still undiagnosed in Europe, and researchers have calculated that the ratio between diagnosed and undiagnosed patients is as high as 1:7.89 Increased physician awareness of the clinical range of this disorder and a continued high threshold of suspicion are, therefore, needed. Researchers have shown that case-finding by measurement of antiendomysial antibodies or hTTG

Dietary treatment

The only proven treatment for coeliac disease is strict and life-long adherence to a gluten-free diet. All food and drugs that contain gluten from wheat, rye, barley, and their derivatives must be eliminated because even small amounts can be harmful. Gluten contamination in gluten-free products cannot be completely avoided; results of a double-blind placebo–control trial established that 10 mg gluten per day is tolerated whereas 50 mg is harmful.110 Individual variability between patients,

Complications

Results of studies from Italy121 and Sweden122 showed a twofold increased mortality in patients with coeliac disease, whereas this risk was only marginally raised in the UK.123 The risk of death rose with increasing delay in diagnosis and in patients with poor dietary compliance; non-Hodgkin lymphoma was the main cause of death.121 Patients diagnosed with the condition in childhood have a threefold increased risk of long-term mortality.124 However, this excess was mostly attributable to

Future directions

Improved understanding of the molecular basis of coeliac disease has enabled researchers to suggest alternatives to a gluten-free diet. These novel treatments are aimed at blunting the immune stimulatory effects of gluten (figure 6). However, we emphasise that some of these drugs (tissue-transglutaminase-inhibitors and monoclonal antibodies) have a poor safety profile, and their hypothetical use could, thus, be reserved for complicated forms of the disease.

Alternative approaches to manage the

Search strategy and selection criteria

We searched Medline using the medical subject heading (MeSH) terms “coeliac disease” and “celiac disease” for articles published between January, 1998, and January, 2009, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of review articles on coeliac disease.

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