Pathogenesis of coeliac disease: Implications for treatment

Abstract

Coeliac disease (CD) is an enteropathy, characterised by villous atrophy, which occurs in genetically susceptible individuals. It affects mainly the proximal small intestine, and is caused by an intolerance to cereal storage proteins found in wheat, barley and rye. Due to earlier diagnosis, and the recognition of ‘silent’ or ‘latent’ forms of the disease, the very severe symptoms that were seen previously are not very common now[1]. Malabsorption, with steatorrhoea and weight loss, occur less frequently. Anaemia, vitamin deficiencies, complications of pregnancy and associated autoimmune diseases, such as insulin dependent diabetes mellitus or thyroid disease are often the clues which lead to the diagnosis of coeliac disease. Coeliac disease affects people from all ethnic groups, though it is most common in people originating in Europe, including people in North America and Australia. It is rarely seen in people from an Afro-Caribbean background[2]. In the past, the prevalence of coeliac disease has been thought to be 1 in 1500 of the population in Western countries, based on the number of identified cases. However, recent screening studies of blood donors has shown a far higher prevalence of 1 in 250 in Sweden[3] and the United States [4]. In Italy, a population screening study of 17000 school children between the ages of 6 and 15 revealed a prevalence rate of 1 in 184[5]. This appears to be uniform throughout most of Europe, with some areas of higher incidence, such as the west coast of Ireland. It affects males and females equally. The reason for this discrepancy between clinically apparent cases, and the number of individuals with positive screening results, lies in the concept of the ‘coeliac iceberg’[2]. The majority of people with coeliac disease are symptom-free, or have only mild symptoms, and do not approach a health care professional for a diagnosis. These individuals have ‘silent’ coeliac disease, if they have abnormal screening antibodies and an abnormal small bowel biopsy, but no symptoms. Individuals with abnormal screening antibody tests, but a normal small bowel biopsy and no symptoms, have ‘latent’ coeliac disease[6]. Thus, there are large numbers of people who are undiagnosed, in the ‘coeliac iceberg’ analogy this would be the vast portion of the iceberg which is not visible, whereas the diagnosed individuals with symptoms form the tip of the iceberg (Figure ​(Figure11). Figure 1 The coeliac iceberg. After A Ferguson[2] HISTOPATHOLOGY In the small intestine, the abnormalities are most marked proximally and decrease in severity with distal progression through the small intestine. In severe cases, the lesion may affect the ileum and even the stomach and rectum[7]. Flattening of the mucosa can vary from mild, through partial villous atrophy, to a total absence of villi. Classically, in untreated celiac disease, there is a flat mucosa with no villi (total villous atrophy), but more usually there is a reduction in the normal villous height, resulting in the villous height: crypt depth ratio being reduced from its normal value of between 3-5∶1. The thickness of the mucosa is usually increased because of crypt hyperplasia. The surface epithelial cells become pseudostratified compared to their normal tall columnar shape with resultant fall in enterocyte height. Crypt mitotic activity is no longer confined to the base and, although the histological appearance is usually normal, crypt abscesses have been described. Cell migration from the crypt base to the villous tip is reduced in untreated coeliac disease to 12-24 h compared with the normal 3-5 d. There is a chronic inflammatory cell infiltrate in the mucosa of the small intestine in untreated coeliac disease with a rise in the number of plasma cells in the lamina propria. There is an increase in the ratio of intra-epithelial lymphocytes to surface enterocytes in active disease. Most of the intra-epithelial lymphocytes express the common leucocyte antigen CD3, 70% express the suppressor/cytotoxic leucocyte antigen CD8, 5% express the helper/inducer CD4 phenocyte, whereas 20% of the cells are CD3+ve, CD4-ve and CD8-ve. Most of these cells express the more primitive γ/δ rather than the more usual α/β T-cell receptor. This results in a significant increase in the number of γ/δ T-cell receptor+ve lymphocytes in the surface epithelium of the small intestine, both in treated and untreated coeliac disease[7].