Overview and pathogenesis of celiac disease

Abstract

Celiac disease is characterized by small intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals following the dietary ingestion of “gluten.” The pathogenesis of disease involves interactions between environmental, genetic, and immunologic factors. 1 This brief overview of celiac disease and its pathogenesis is designed to place this disease, and current views of its pathogenesis, in a context appropriate for further consideration within the framework of questions being posed by the NIH Consensus Conference on Celiac Disease. Pathology and Clinical Symptoms First, a brief overview of disease pathology and clinical symptoms. The luminal surface of a small intestinal mucosal biopsy specimen from a healthy subject and an individual with celiac disease with total villous atrophy, as viewed through a dissecting microscope, are shown in Figure 1A and 1B, respectively. The normal biopsy specimen shows abundant villi (looking much like the shag household carpets of a prior era), whereas the biopsy specimen from the patient with celiac disease shows a complete loss of villi, with a flat mucosal surface accentuated by ridges and numerous openings of the crypts onto the luminal surface. Microscopic analysis of a normal H&E-stained, small intestinal mucosal biopsy specimen is shown in Figure 1C. Characteristic features include tall villi lined by a single layer of columnar epithelial cells with basally oriented nuclei, a “smattering” of intraepithelial lymphocytes (IEL) occurring at a ratio of approximately 1 per 6 –10 epithelial cells, a normal complement of lymphocytes and plasma cells in the lamina propria consistent with the normal “physiologic inflammation” of the small intestine, and a villous to crypt ratio of 4 –5:1. Contrast that biopsy specimen with the biopsy specimen from a celiac disease patient with total villous atrophy as shown in Figure 1D. The latter reveals a complete loss of villi, markedly abnormal squamoid surface epithelial cells, an increase in intraepithelial lymphocytes, a chronic lymphocyte and plasma cell infiltrate in the lamina propria, and marked crypt hyperplasia with increased crypt mitoses. The pathology shown in this celiac biopsy specimen reflects the more severe end of the pathologic spectrum of disease, which, as indicated in Figure 2, can vary markedly among affected individuals. Just as the pathology can vary markedly among patients, so can the spectrum of clinical symptoms, which can range from severe to subtle (Figure 3). The proportion of individuals presenting with more dramatic symptoms of diarrhea, severe weight loss, and malnutrition is decreasing when compared with those presenting with mild or minimal symptoms or asymptomatic individuals in which disease is discovered only when investigating nongastrointestinal symptoms, for example, iron deficiency anemia or osteopenia. 2 A more detailed explanation of the clinical presentation of celiac disease in children and adults is presented in later articles in this series. Pathogenesis of Celiac Disease