Celiac disease is a systemic immune-mediated disorder. In genetically susceptible individuals, it is triggered by dietary gluten. Gluten is a complex of proteins that are found in wheat, rye, and barley. Gliadin is the water-soluble component in gluten. Celiac disease is extremely common, affecting 0.6% to 1% of the worldwide population. However, only a small percentage of cases of celiac disease are recognized. Its prevalence is higher in women, with increased incidence in individuals with an affected first-degree relative, or a relative with type 1 diabetes, Hashimoto thyroiditis, or other autoimmune disease. Importantly, genetic background greatly influences the predisposition to celiac disease. In 90% of patients with celiac disease, the HLA-DQ2 haplotype is expressed (which is present in only approximately one third of the general population). The HLA-DQ8 haplotype is expressed in 5% of the patients with celiac disease. This genetic predisposition occurs because the HLA-DQ2 and HLA-DQ8 haplotypes are expressed on the surface of antigen-presenting cells that bind activated (deamidated) gluten peptides. The HLA-DQ2 and HLA-DQ8 haplotypes are necessary, but their presence alone is not sufficient for the development of celiac disease. There are dozens of non-HLA genes that confer predisposition to celiac disease, and most of these are involved in the inflammatory and immune response.
Celiac disease is an immunologic disorder caused by immune reactions triggered by gluten and related proteins that are components of wheat, barley, and rye grain products.
Patients with celiac disease have chronic inflammation of the proximal small intestinal mucosa. The inflammation can heal when foods containing gluten are excluded from the diet. The inflammation returns if foods containing gluten are reintroduced. Gluten-associated storage proteins derived from wheat, barley, and rye undergo partial digestion in the upper gastrointestinal tract. The partial digestion results in the generation of derivatives of the native peptides, and these specific peptides can elicit an immune response. The enzyme transglutaminase deamidates glutamine to negatively charged glutamic acid residues in gliadin peptides, which then stimulate the immune response and the subsequent intestinal injury.
Mildly affected individuals may have symptoms such as bloating, irregular bowel movements, and cramps (often referred to as irritable bowel syndrome). Celiac disease patients may present with malabsorption of certain essential nutrients, including iron. About 5% of iron deficiency in adults is thought to be due to celiac disease. Malabsorption of folate and vitamin D, which may present clinically as osteoporosis, can also occur.
Laboratory testing for celiac disease is summarized in Table 15–2.
Table 15–2Commonly Used Diagnostic Tests for Celiac Disease ||Download (.pdf) Table 15–2 Commonly Used Diagnostic Tests for Celiac Disease
|Test ||Advantages ||Disadvantages |
|Tissue transglutaminase (tTG) IgA antibodies ||Most reliable noninvasive test and first-level screening test High sensitivity and specificity ||Falsely negative with IgA deficiency (3% of patients with celiac disease) May be negative if on low-gluten diet |
|Tissue transglutaminase (tTG) IgG antibodies ||Useful in patients with IgA deficiency ||Widely variable sensitivity and specificity |
|IgA antiendomysial antibodies ||May be useful in patients with borderline results for tTG antibodies ||Sensitivity for celiac disease less than IgA anti-transglutaminase antibody test |
|IgG deamidated gliadin peptide antibodies ||Useful in patients with IgA deficiency and in young children ||Not as sensitive or specific as tTG IgA antibodies |
|HLA-DQ2 or HLA-DQ8 ||High negative predictive value for celiac disease ||Test is complex and expensive |
|Small bowel biopsy ||Reliable test, considered gold standard Reflects response to treatment ||Requires endoscopy and biopsy Very expensive |
A serologic test for IgA anti-tissue transglutaminase (tTG) antibodies is recommended as the initial testing for individuals who do not have a concomitant IgA deficiency. This is the most widely used test and has a sensitivity and a specificity over 98%, especially now that human tTG is used in the test as a reagent. As many as 3% of those with classic celiac disease have a deficiency of IgA, which results in a falsely negative test result. In a person with a high suspicion for celiac disease and a negative anti-tTG result, measurement of IgA to determine if the patient is IgA deficient is recommended. In persons with IgA deficiency, IgG, instead of IgA, anti-tTG antibodies can be measured. Another alternative for IgA-deficient patients is the measurement of the IgG deamidated gliadin peptide antibodies. Tests for antibodies to deamidated gliadin peptides are less sensitive and less specific in adults for diagnosis of celiac disease, but they are more sensitive than anti-tTG assays in children. Antibody tests to gliadin are less likely to be positive in milder cases, and, like the other serologic tests, often become negative when gluten is eliminated from the diet. Some patients may be monitored with antibody levels to gliadin to monitor compliance with treatment.
The endomysium is a connective tissue that ensheaths each individual muscle fiber. Antiendomysial antibodies are present in patients with celiac disease. They are useful in the diagnosis of the disease, but do not cause any direct symptoms associated with muscles. The presence of antiendomysial antibodies is nearly 100% specific for active celiac disease, but these antibodies are found in other autoimmune diseases, and for that reason this antibody measurement should be used as a confirmatory test for borderline cases initially tested with an anti-tTG antibody assay.
Patients with celiac disease can be differentiated from patients with simple gluten sensitivity and patients with wheat allergy because the antibodies found in celiac disease are absent in those with gluten sensitivity or wheat allergy. In addition, for celiac disease, the interval between exposure to gluten and onset of symptoms is weeks to years. This is in contrast to simple gluten sensitivity where the interval between exposure and onset of symptoms is hours to days, and wheat allergy where the interval is minutes to hours.
The diagnosis of celiac sprue currently requires endoscopy with biopsy of the duodenum. In severe cases, there is atrophy of villi and flattening of the mucosa, but milder cases may show only lymphocytes infiltrating the mucosa. In children, recent guidelines suggest that a biopsy may not be required if there are typical symptoms and a high titer of anti-tTG antibodies, along with HLA-DQ2 and/or HLA-DQ8 genotypes.