Celiac disease is a chronic, immune‐mediated enteropathy that is perpetuated by the ingestion of gluten in genetically predisposed individuals. This definition encompasses many key features of the disorder. First, it is a chronic disease and, while individuals are not born with celiac disease, once triggered, it tends to be a life‐long disorder. Second, it is an autoimmune disorder where adaptive immune activation leads in turn to activation of innate immune responses, with tissue inflammation and destruction. Third, celiac disease is triggered by antigenic peptides from wheat and evolutionarily related grains, collectively termed “gluten.” Removal of these antigens from the diet leads to disease remission in most individuals. Finally, the production of autoantibodies, classically to intestinal transglutaminase, which is tissue transglutaminase type 2, but also to other local antigens and related transglutaminases, is a unique feature of celiac disease, and has led to its designation as an autoimmune disorder.

Celiac disease is a relatively well‐understood chronic inflammatory disorder and many details are known about genetic risk and disease pathogenesis. Elegant studies have been performed to define several critical steps in the progression of the disease from gluten uptake in the mucosa, to its processing by tissue transglutaminase to form deamidated gliadin peptides and their presentation on the human leukocyte antigen haplotypes DQ2 or DQ8 to activate gliadin‐specific T‐cell responses. With increasing inflammation, there is infiltration of increased numbers of intraepithelial lymphocytes, followed by disruption of normal villus architecture with crypt hyperplasia and villous shortening (Figure 23.1).

Celiac disease can present with a variety of signs and symptoms, and so testing can be considered in a number of circumstances (Table 23.1). For all individuals in whom celiac disease is being considered, serological testing should be the initial step in evaluation (Figure 23.2). IgA‐endomysial antibody (EMA), IgA‐tissue tTG, and IgA or IgG DGP testing all have sensitivities and specificities above 90% with most assays and in most populations. tTG‐IgA testing is now the default test for celiac disease; however, EMA and DGP are valid alternatives and may be used depending on local cost and expertise. While diagnosis without biopsy is becoming more widely accepted, at this time, confirmation of diagnosis with endoscopy and biopsy is recommended in most patients, unless there is a medical contraindication to this procedure.

Villus atrophy is not exclusive to celiac disease and a differential diagnosis should be considered, particularly in seronegative patients (Box 23.1). Patients with more mild degrees of villus damage may not have celiac disease, and further testing may be indicated prior to commencing a gluten‐free diet (Figure 23.3). Among patients who are already maintaining a gluten‐free diet at the time of evaluation, a gluten challenge may be necessary (Figure 23.4).

Celiac disease is a global disorder, reported in almost every population in which testing has occurred. Epidemiological studies in Europe and the United States indicate that celiac disease has a prevalence of approximately 1%. Overall, there have been dramatic increases in the estimated prevalence of celiac disease in Europe, America, and elsewhere. The only treatment for celiac disease at this time is the gluten‐free diet (Box 23.2). While most patients respond adequately to treatment, the burden of maintaining a lifelong gluten‐free diet is high and many patients do not achieve histological remission (Table 23.2, Figure 23.5). Complications of celiac disease, which usually occur in the setting of active mucosal disease, include refractory celiac disease, ulcerative jejunitis, non‐Hodgkin lymphoma, enteropathy‐associated T‐cell lymphoma (EATL), and small intestinal adenocarcinoma (Figure 23.6).

Acknowledgments

The authors gratefully acknowledge the contributions of the author of the previous edition of this chapter, Dr Ciaran Kelly, and Melinda Dennis RD for her contributions to the Yamada Textbook chapter on celiac disease.

Risk of celiac disease/strength of recommendation for testing	Manifestation/presentation	Notes
High: Testing always warranted Negative serological test result may not adequately rule out celiac disease	Chronic gastrointestinal symptoms with a family history of celiac disease or a personal history of autoimmune disease Skin lesions consistent with dermatitis herpetiformis Chronic diarrhea Failure to thrive in children Iron deficiency anemia refractory to oral supplementation	Risk of celiac disease in most studies 10% or higher
Medium: Testing generally warranted Negative serological test result sufficient to rule out celiac disease	Irritable bowel syndrome Elevated liver function tests Iron deficiency anemia Lactose intolerance Fatigue/lethargy Chronic gastrointestinal symptoms without a family history of celiac disease or a personal history of autoimmune disease Peripheral neuropathy Idiopathic ataxia Dental enamel defects Fertility abnormalities Down or Turner syndrome IgA deficiency Microscopic colitis	Risk of celiac disease estimated to be 4–10%
Low: Testing recommended only after exclusion of more likely etiologies or in setting of coexisting risk factors Negative serological test result sufficient to rule out celiac disease	Osteopenia/osteoporosis Chronic fatigue syndrome Heartburn Acute or chronic pancreatitis Alopecia Myalgias/arthralgias Autoimmune liver disease Personal history of autoimmune disease or connective tissue disease without suggestive symptoms Headaches including migraines Mood disorders Epilepsy	Estimated risk of celiac disease less than 4%