Mortality in Celiac Disease, Intestinal Inflammation, and Gluten Sensitivity

Abstract

CELIAC DISEASE DEVELOPS IN GENETICALLY PREDISposed individuals as a response to ingested gluten. Gluten is the term for the storage proteins of the cereal grains wheat, rye, and barley. While virtually 100% of the population ingests these grains in one form or another and 30% to 40% of the population carry the genetic markers of the disease (HLA-DQ2 or type 8), only 2% to 3% of those with genetic markers develop the disease. This indicates that other genetic factors and environmental precipitants are necessary for disease expression. These factors are largely unknown, although breastfeeding, timing of gluten introduction, and gastrointestinal infections in childhood have been incriminated, at least in the development of childhood celiac disease. The diagnosis of celiac disease is dependent on finding characteristic, although not specific, pathological findings in duodenal biopsies. These changes include inflammatory changes within the small-intestinal epithelium (intraepithelial lymphocytosis) and the lamina propria as well as various degrees of villous atrophy. A range of pathological abnormalities exists, from intraepithelial lymphocytosis with normal villous architecture to total villous atrophy, all of which are considered part of the spectrum of gluten enteropathy or celiac disease. However, there are several causes of intraepithelial lymphocytosis without villous atrophy in addition to celiac disease, such as Helicobacter pylori infection and tropical sprue. It is therefore difficult to diagnose celiac disease in the setting of intestinal inflammation when villous atrophy is absent. But in some clinical settings, such as the presence of symptoms, positive serologic results, and even the appropriate HLA type, patients with these inflammatory changes receive a diagnosis of celiac disease. Serologic blood tests that include antigliadin, tissue transglutaminase (tTG), and endomysial antibodies are used for triaging individuals for endoscopic biopsy. The tTG and endomysial antibodies are sensitive and specific for celiac disease, while antigliadin antibodies are not as sensitive or specific. Celiac disease is common, occurring in about 1% of the population, although the majority of cases are undiagnosed. The number of persons actually diagnosed as having celiac disease varies from country to country, depending on physician awareness of the varied clinical manifestations and the availability of blood tests for the condition. The rate of diagnosis is high in some European countries such as Finland, where in some regions 70% of cases are diagnosed. Within the United States, the rate of diagnosis is increasing, both in adults and children, although only a small fraction (estimated at 5%) of cases are diagnosed. Recent evidence from both Finland and the United States has demonstrated that the prevalence of celiac disease has increased markedly over a relatively short time. In the United States, the prevalence of celiac disease has increased 4-fold in the last 50 years. These data are based on the analysis of stored serum samples and reflect a true increase in the prevalence of the disease, not just the number of individuals who are given diagnoses. The reason for this increase is not clear but may be related to environmental factors such as the changing nature of gluten or other factors related to diet. Accompanying this increase in disease prevalence is a change in the clinical manifestations, so that the classic presentation of diarrhea and malabsorption syndrome is now less common than other presentations. The disease now manifests more often as a multisystem disorder. Anemia, osteoporosis, peripheral neuropathy or ataxia, irritable bowel syndrome, and dyspepsia are all possible presentations. Many patients are asymptomatic, with the disease detected by screening performed because of their presence in a highrisk group such as being a family member or having an associated autoimmune disease, type 1 diabetes, or Down syndrome. Increasingly, those with autoimmune thyroid disease are also screened. Patients with undiagnosed or diagnosed celiac disease appear to have an increased mortality risk. Based on studies that have examined stored serum samples for tTG antibodies and correlated the results with mortality data, those with