Key Points
Disease summary:
Celiac disease (CD) is a chronic inflammatory disease of the small intestine manifests as a dysregulated immune response to a known environmental trigger (gluten and its related proteins) in genetically susceptible individuals. The mainstay of treatment is a gluten-free diet.
CD is a common disease with a prevalence of up to 1% in Caucasian populations, but remains underdiagnosed. Classical presentation with malabsorption and gastrointestinal (GI) symptoms such as diarrhea or abdominal discomfort is relatively rare; more commonly, patients have vague symptoms or extraintestinal presentations including dermatitis herpetiformis, anemia, osteoporosis, short stature, infertility, fatigue, or transaminitis.
Serologic testing can aid in diagnosis of CD. The most sensitive and specific tests are antitissue transglutaminase (anti-tTG) or antiendomysial IgA antibodies. However, the gold standard of diagnosis is still demonstration of villous atrophy on duodenal biopsy and a clinical response to a gluten-free diet. Nearly all CD patients have HLA-DQ2 or HLA-DQ8 although a significant percentage of the normal population also carries these human leukocyte antigen (HLA) alleles; testing for HLA-DQ2 or DQ8 has excellent negative predictive value. A high prevalence of IgA deficiency mandates that when serology is negative but there is high clinical suspicion of CD, measurement of total IgA levels is indicated.
Patients with CD have an increased risk of malignancy (small intestinal adenocarcinoma and enteropathy-associated T-cell lymphoma). A subset of CD patients has refractory disease that will not respond to a gluten-free diet and is associated with a poorer prognosis.
CD is associated with other immune-mediated diseases, such as type 1 diabetes and inflammatory bowel disease, suggesting a common genetic background for these disorders.
Differential diagnosis:
Collagenous sprue, Whipple disease, tropical sprue, Crohn disease, food intolerance (such as lactose), intestinal lymphoma, pancreatic insufficiency, bacterial overgrowth
Monogenic forms:
No single gene is known to cause CD.
Family history:
CD has a prevalence of 5% to 15% among first-degree relatives of affected patients.
Twin studies:
Monozygotic twins have a 75% concordance rate in CD; dizygotic twins have an 11% concordance rate.
Environmental factors:
The known triggering environmental antigen in CD is gluten, the protein found in wheat, and related proteins found in barley and rye. Gluten is composed of gliadin and glutenin proteins and has a high content of glutamine. tTG enhances the immunogenicity of gluten by deamidating glutamine, allowing gluten peptides to bind more strongly to HLA-DQ2 or DQ8 molecules on antigen-presenting cells (APCs) which then activate CD4+ T cells. A possible role for intestinal infections, such as rotavirus, in increasing the risk of CD has been implicated in the pathogenesis of CD.
Genome-wide associations:
Genome-wide association study (GWAS) has confirmed the strong association of HLA-DQ2 and DQ8 with CD and uncovered many other susceptibility loci in CD, many of which encode genes involved in the immune response.
Pharmacogenomics:
Pharmacogenetic testing currently does not have a role in CD.
Diagnostic Criteria and Clinical Characteristics
Diagnostic testing for CD while the patient is on a gluten-containing diet.
Serologic testing is often the first tests sent to diagnose CD. IgA antiendomysial antibodies and IgA antitissue tTG antibodies both have high sensitivity and specificity in screening for CD. Antiendomysial antibodies have a sensitivity of 90% to 97% and a specificity approaching 100%; anti-tTG antibodies have a sensitivity of 90% to 98% and specificity of 95% to 99%. Anti-tTG is preferred as testing for antiendomysial antibodies and is more operator dependent. Serum levels of these antibodies correlate with the degree of villous atrophy, and these tests may therefore have decreased sensitivity in milder disease. In contrast, IgA antigliadin antibodies have much lower sensitivity (no higher than 80%) and specificity (80%-90%).
IgA deficiency is 10 to 15 times more common among patients with CD than in the general population with a prevalence of up to 3% and is important to consider in patients with negative IgA antiendomysial or anti-tTG antibodies with a high clinical suspicion for CD. If total IgA is low, serologic testing for CD can be performed using IgG antiendomysial or IgG anti-tTG antibodies. Some clinicians send total IgA levels with initial antiendomysial or anti-tTG antibody screening tests.
The gold standard for diagnosing CD remains intestinal biopsy. Endoscopy should be performed even if serology is negative if there is high clinical suspicion. Biopsies should be obtained from the descending duodenum. Since the disease may be patchy, at least four biopsies should be taken. Endoscopy in patients with CD may demonstrate gross signs of villous atrophy including atrophic mucosa or scalloping of duodenal folds. However, these findings are neither sensitive nor specific for CD. Histology can range from partial to total villous atrophy. Other findings in CD include increased numbers of intraepithelial lymphocytes and hyperplastic, enlarged crypts, and increased numbers of inflammatory cells in the lamina propria.
Genetic testing is helpful when other diagnostic tests are inconclusive. Nearly all patients with CD have HLA-DQ2 or HLA-DQ8 molecules (>99%). As the prevalence of these markers in the general population is high (30%-40%), HLA testing has poor specificity for CD and a high negative predictive value (near 100%). If these markers are absent, the diagnosis of CD is virtually excluded.
Patients with positive histology must also demonstrate a clinical response to a gluten-free diet. If there is no response to treatment, other causes of villous atrophy should be considered. These include, but are not limited to, collagenous sprue, Whipple disease, tropical sprue, giardiasis, HIV enteropathy, eosinophilic gastroenteritis, Zollinger-Ellison syndrome, radiation- or chemotherapy-induced enteritis, Crohn disease, intestinal lymphoma, or food intolerance.
The clinical presentation of CD in adults can vary greatly. It has been suggested that CD can be divided into several distinct phenotypes given the wide range of disease presentations. Patients with classic CD present with GI symptoms including diarrhea, steatorrhea, flatulence, and abdominal pain or flatulence. Classic CD presents similarly to irritable bowel syndrome (IBS); the diagnosis of CD should be considered in individuals meeting diagnostic criteria for IBS as the prevalence of CD in this population is increased more than fourfold compared to patients without IBS. In CD, these symptoms may be accompanied by other signs of malabsorption including weight loss, anemia, and vitamin deficiencies (eg, folate, vitamin D, calcium).
CD most commonly presents in an atypical form in which GI symptoms are mild or absent. Patients may present with extraintestinal findings such as iron deficiency, fatigue, osteoporosis, short stature, infertility, unexplained elevated liver enzymes, arthritis, dental enamel defects, aphthous ulcers, or neurologic symptoms such as ataxia, neuropathy, or migraine. Up to 14% of patients with iron deficiency anemia of unclear origin have CD.
Silent CD includes asymptomatic individuals found to have gluten-induced villous atrophy either after a positive serologic screening test or an incidental finding on endoscopy and biopsy. Lastly, patients with a previous diagnosis of CD that are now on a gluten-free diet without villous atrophy have latent disease.
6 is associated with a number of other disorders, many of which are autoimmune diseases. Dermatitis herpetiformis is another form of gluten sensitivity characterized by a pruritic, papulovesicular rash that affects up to 20% of CD patients and typically responds to a gluten-free diet. Other disorders associated with CD include type 1 diabetes, autoimmune thyroid disease, Addison disease, autoimmune hepatitis, primary biliary cirrhosis, autoimmune myocarditis, Sjögren syndrome, and inflammatory bowel disease. For example, the prevalence of CD in patients with type 1 diabetes ranges from 2% to 5%. Neurologic disorders such as peripheral neuropathy, headache, depression, ataxia, and epilepsy also appear to be associated with CD. Patients with osteoporosis have a significant prevalence of CD, ranging from 1% to 3.4%. CD also appears to be more common in patients with Down syndrome, Turner syndrome, and Williams syndrome.
CD is associated with a modest increase in all-cause mortality and may be increased in patients not adhering to a gluten-free diet. Some of the serious complications of CD include enteropathy-associated T-cell lymphoma, adenocarcinoma of the small intestine, and refractory CD. CD patients have an increased risk of both intestinal and extraintestinal non-Hodgkin lymphoma. Enteropathy-associated T-cell lymphoma is more common in older CD patients, develops in the proximal small intestine, and is associated with a poor prognosis. The diagnosis should be considered in patients with relapse of CD symptoms after response to a gluten-free diet. CD also increases the risk of proximal small bowel adenocarcinoma. About 5% of CD patients will develop refractory CD in which symptoms persist despite adherence to a gluten-free diet. Refractory CD can be characterized as type 1 or type 2. Type 1 is characterized by expansion of phenotypically normal intraepithelial lymphocytes. In contrast, intraepithelial lymphocytes in type 2 disease have an abnormal phenotype, lacking surface expression of CD3 and CD8. Patients with type 2 refractory CD have an increased risk of developing enteropathy-associated T-cell lymphoma or ulcerative jejunitis and have a high mortality rate (37%-60% within 5 years). A subset of patients with refractory CD responds to corticosteroid treatment.
