Narrative Review: Celiac Disease: Understanding a Complex Autoimmune Disorder

Once considered a rare childhood disorder, celiac disease is now known to be a common condition that may have multiple complications. Nevertheless, the disease remains widely underrecognized. Use of new serologic markers in the diagnosis of celiac disease, in particular antitransglutaminase antibody, has resulted in more efficient screening. Information on the pathogenic mechanism of the autoimmune response in celiac disease is emerging, although many aspects remain unclear. We discuss current concepts in the clinical presentation and diagnosis of celiac disease; the usefulness of serologic markers, including the sensitivity and specificity of available tests; the pathogenesis of the disease; and the association of celiac disease with other disorders. Celiac disease is one of the most common immune-mediated disorders. Its presence has been documented in North and South America, Europe, north Africa, south and west Asia, and Australia (1, 2). Large studies in the United States and Europe show the prevalence of the disease to approach 1% (3-6). Celiac disease is triggered by ingestion of wheat gluten and related cereal proteins, particularly those in rye and barley. These molecules induce an inflammatory response in the small intestine, resulting in villous atrophy, crypt hyperplasia, and lymphocytic infiltration (2). Elimination of gluten and related proteins from the diet leads to clinical and histologic improvement. A strong genetic susceptibility is demonstrated by a 75% concordance rate among monozygotic twins (7). This relationship is due in part to close genetic linkage to specific class II human leukocyte antigens (HLA). Human leukocyte antigen-DQ2 is expressed in about 95% of patients with celiac disease, and HLA-DQ8 is found in most of the remainder (2). The DQ2 and DQ8 molecules confer susceptibility to celiac disease by presenting specific gluten peptides to T cells of the immune system in the intestine (8-10). Celiac disease is also strongly associated with the presence of antibodies against gluten proteins and of autoantibodies to connective tissue components, the main target of which is transglutaminase 2 (also known as tissue transglutaminase). Clinical Presentation The clinical presentation of celiac disease varies greatly and ranges from asymptomatic to severe malnutrition. The most common manifestations of celiac disease include abdominal pain, increased frequency of bowel movements, weight loss, bone disease, anemia, and weakness. Celiac disease is sometimes divided into clinical subtypes. The terms symptomatic or classic apply to cases that meet the classic features of celiac disease, which include chronic diarrhea, abdominal distention and pain, weakness, and sometimes malabsorption. In contrast, in the now-common atypical form of the disease, gastrointestinal symptoms may be absent or less pronounced; instead, extraintestinal features, such as anemia, osteoporosis, short stature, infertility, and neurologic problems, are more prominent (11-41) (Table 1). Patients with asymptomatic or silent celiac disease lack classic or atypical symptoms but have villous atrophy that may be discovered during endoscopy or intestinal biopsy for other reasons, or as a result of serologic screening. Because atypical presentations are increasingly found to predominate, celiac disease is now considered to resemble a multisystem disorder rather than a mainly gastrointestinal one (42, 43). Table 1. Disorders Associated with Celiac Disease Diagnosis and Management Current diagnostic criteria for celiac disease in clinical practice are based on revised guidelines proposed by the European Society for Paediatric Gastroenterology and Nutrition, which have been extrapolated to adults (44). According to these guidelines, celiac disease is present if histologic changes are found on intestinal biopsy while the patient consumes a gluten-containing diet and unequivocal clinical improvement occurs while he or she consumes a gluten-free diet. Figure 1 shows a possible algorithm for diagnosing celiac disease that is based on the European Society for Paediatric Gastroenterology and Nutrition criteria (44) and on recommendations from the National Institutes of Health Consensus Development Conference on Celiac Disease (45). Patients usually undergo tests for serologic markers once celiac disease is suspected, either because characteristic symptoms are present or because they are in an at-risk group, such as having disorders associated with celiac disease (Table 1) or being a first-degree relative of a person with the disease. Measurement of antitransglutaminase 2 (or antiendomysial) antibodies of the IgA isotype is more sensitive and specific for celiac disease than is the IgG isotype and is recommended for initial screening. However, IgA deficiency occurs in 1.7% to 2.6% of patients with celiac disease, which is a 10- to 16-fold increase over that in the general population (35). It is therefore helpful to also measure total IgA. If IgA deficiency is found, measurement of IgG class antitransglutaminase 2 (or antiendomysial) and antigliadin antibodies is recommended. Figure 1. Proposed algorithm for evaluation of patients in whom celiac disease is suspected. If results of testing for IgA antitransglutaminase 2 or antiendomysial antibodies is positive, if IgA deficiency is found and results of testing for IgG antibody (antitransglutaminase 2, antiendomysial, or antigliadin antibodies) is positive, or if results of serologic testing are negative but clinical suspicion is high, intestinal biopsy should be performed (Figure 1). Because the disease may be patchy, as seen on chromoendoscopy and magnification endoscopy (46, 47), an adequate number of tissue samples (4 to 6 pieces) must be obtained (48, 49). Such sampling will further ensure that some sections will be oriented correctly to determine the degree of villous atrophy needed to make the diagnosis, whereas other pieces allow assessment of intraepithelial lymphocytosis, epithelial disarray, and degree of inflammation. Biopsy samples obtained with standard-size forceps from the descending duodenum at the level of the ampulla of Vater are sufficient for diagnosis (50). Interest is increasing in video capsule endoscopy for assessment of small-intestinal diseases, although use of this technique in patients with celiac disease has not been studied. Characteristic histologic features of celiac disease include varying degrees of villous atrophy, with hyperplasia of the crypts and increased intraepithelial lymphocyte count. The criteria proposed by Marsh are often used to grade the disease (from 0 to 4) in terms of these features (51). Most symptomatic patients have partial, subtotal, or total villous atrophy, which are Marsh type 3 lesions. Positive identification of these abnormalities leads to a presumptive diagnosis of celiac disease and institution of a gluten-free diet. Clear clinical improvement while the patient is following the diet yields a definitive diagnosis. The serum antibodies generally disappear by 6 to 12 months, although they are not necessarily reliable indicators of the mucosal response (52, 53). When patients do not present with the classic clinical symptoms of celiac disease, a second biopsy that shows histologic improvement confirms the diagnosis. Gluten challenge is not considered necessary for diagnosis, except in patients for whom no initial diagnostic biopsy was done or results of biopsy are unclear or uncharacteristic of celiac disease. In such cases, biopsy is repeated after clinical relapse subsequent to gluten challenge, or after 3 to 6 months if gluten challenge does not lead to symptoms (44). Patients should be told that they may have a severe reaction to the gluten challenge. Of note, diagnosis of celiac disease based solely on serologic markers is not yet accepted, and identification of the characteristic mucosal abnormalities on intestinal biopsy is required. However, intestinal biopsy can also yield false-negative results, either because the intestinal damage is patchy or because mucosal changes are not detectable on light microscopy (2, 54). If results of biopsy are negative but serologic tests are positive and celiac disease is strongly suspected, the results of the biopsy should be reviewed with an expert gastrointestinal pathologist before additional biopsy is considered. In addition, if histologic examination yields equivocal results, it is useful to proceed with HLA typing. Although about 30% of the general population has the HLA-DQ2 or HLA-DQ8 markers, nearly all patients with celiac disease have them (55). Therefore, a negative result for both markers has an excellent negative predictive value for the disease (56). Table 2 summarizes issues that clinicians often face in diagnosing celiac disease and ways to manage them. Table 2. Common Pitfalls in Diagnosis of Celiac Disease The mainstay of treatment of celiac disease is strict lifelong adherence to a gluten-free diet, in which the patient avoids food products containing wheat, rye, or barley. Even though various studies have found oat to be generally well tolerated (57), some patients appear to be sensitive to it, and the presence of oat-specific intestinal T cells has been demonstrated in persons with celiac disease (58). More important, concern about contamination from the above-mentioned cereals in commercial preparations of oat has led to reluctance in recommending it (57, 59). Commonly substituted grains in the gluten-free diet include rice, corn, quinoa, and buckwheat. Although use of a gluten-free diet safely and effectively manages celiac disease, adherence is not a trivial task in an age in which wheat flour is nearly ubiquitous in foods. Patients whose disease does not respond to dietary therapy should undergo a systematic evaluation (60, 61). The 2 most important points to clarify are whether the patient actually has the disease and whether the patient is truly consuming a gluten