Heterogeneity of Celiac Disease: Clinical, Pathological, Immunological, and Genetic

In this paper we consider recent new data on the pathological features of gluten sensitivity and on the disease‐associated antigens, in the context of a multistage hypothesis that we have been developing for the last five years. This incorporates concepts of oral tolerance induction, mucosal T‐cell and antibody‐mediated injury, and genetic contributions. Until now, there has been complete agreement that the diagnosis of celiac disease must be based on small bowel histology. There are patients with low‐grade gluten‐sensitive enteropathy, in whom the only morphological abnormality is a high count of intraepithelial lymphocytes (IEL). Some, but not all, also have positive serum IgA anti‐endomysium antibody (AEA). With good techniques, in a properly accredited laboratory, in a patient suspected on clinical grounds to have celiac disease, a positive serum IgA AEA test (perhaps, alternatively, high‐titer anti‐transglutaminase by ELISA), is virtually diagnostic of the condition. Our hypothesis of a stepwise pathogenesis of severe gluten‐sensitive enteropathy is re‐examined in the light of these new data. It is evident that there are at least five different levels at which genetic influences may operate.