Celiac disease is a chronic autoimmune disease characterized by malabsorption and diarrhea precipitated by ingestion of food products containing gluten in genetically susceptible persons. Gluten is a protein complex found in wheat, rye, and barley.

Gluten-sensitive enteropathy

Celiac sprue

Nontropical sprue

• The prevalence of celiac disease is 0.5% to 1% in the general population in North America and Western Europe and 5% in high-risk groups such as first-degree relatives of persons with the disease. The prevalence of celiac disease in the U.S. has increased fourfold over the past three decades, but the trend is flattening. The decline in undiagnosed celiac disease may reflect greater public and professional attention to gluten-related issues. Worldwide celiac disease affects 0.6% to 1% of the population. Celiac disease is significantly more common in persons with type 1 diabetes mellitus (DM) and is associated with greater risk of retinopathy and nephropathy in this population.
• Incidence is highest during infancy and the first 36 mo of life (after introduction of foods containing gluten), in the third decade (frequently associated with pregnancy and severe anemia during pregnancy), and in the seventh decade.
• There is a slight female predominance.
• The average age of diagnosis is in the fifth decade of life.
• The risk for celiac disease is 5% to 10% in newborn children of parents with the disease and nearly 20% in siblings.
• It is estimated that only 10% to 15% of persons with celiac disease in the U.S. have been diagnosed.

• Physical examination may be entirely within normal limits.
• Weight loss, dyspepsia, short stature, and failure to thrive may be noted in children and infants.
• Weight loss, fatigue, and diarrhea are common in adults.
• Abdominal pain, nausea, and vomiting are unusual.
• Pallor as a result of iron deficiency anemia is common.
• Atypical forms of the disease are being increasingly recognized and include osteoporosis, short stature, anemia, infertility, and neurologic problems. Manifestations of calcium deficiency, such as tetany and seizures, are rare and can be exacerbated by coexistent magnesium deficiency.
• Angular cheilitis, aphthous ulcers, atopic dermatitis, and dermatitis herpetiformis are frequently associated with celiac disease.
• Table 1 summarizes the clinical spectrum of celiac disease.
• Table 2 summarizes extraintestinal manifestations of celiac disease.
• Disorders associated with celiac disease are summarized in Box 1.

• Celiac sprue is considered an autoimmune-type disease, with tissue transglutaminase (tTG) suggested as a major autoantigen. It results from an inappropriate T-cell-mediated immune response against ingested gluten in genetically predisposed individuals who carry either HLA-DQ2 or HLA-DQ8 genes. There is sensitivity to gliadin, a protein fraction of gluten found in wheat, rye, and barley. In patients with celiac disease, immune responses to gliadin fractions promote an inflammatory reaction, mainly in the upper small intestine, manifested by infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy. The susceptibility to celiac disease may also be related to other environmental factors such as bacterial microbiome and reovirus infection). Table E3 summarizes biomarkers in the diagnosis of celiac disease and monitoring compliance to gluten-free diet.
• Seroconversion to celiac autoimmunity may occur at any time.
• Timing of introduction of gluten into the infant diet in children at risk remains inconclusive. Children initially exposed to gluten in the first 3 mo of life have a fivefold increased risk. Current recommendations are to delay introduction of gluten into the diet of a genetically susceptible infant until 4 to 6 mo of age while the mother continues to breastfeed.
• Trials involving randomized feeding intervention in infants at high risk for celiac disease have shown that as compared to placebo, the introduction of small quantities of gluten at 16 to 24 wk of age did not reduce the risk of celiac disease by 3 yr of age.

• Inflammatory bowel disease
• Laxative abuse
• Intestinal parasitic infestations
• Lactose intolerance
• Other: Irritable bowel syndrome, tropical sprue, chronic pancreatitis, Zollinger-Ellison syndrome, cystic fibrosis (children), lymphoma, eosinophilic gastroenteritis, short bowel syndrome, Whipple disease
• Intestinal lymphoma, tuberculosis, radiation enteritis, HIV enteropathy

• IgA anti-tTG antibody by enzyme-linked immunosorbent assay (tissue transglutaminase [tTG] test) is the best screening serologic test for celiac disease. IgA antiendomysial antibodies (EMA) test is also a good screening test for celiac disease but is best used as a confirmatory test in cases of borderline positive results. In patients with IgA deficiency, the IgG deamidated gliadin peptide (DPG) test (deamidated gliadin peptides) can be used for diagnosis. Screening of close relatives is initially done with polymerase chain reaction (PCR) testing for HLA-DQ2 or HLA-DQ8. Those that are positive should then have serum tTG IgA screening. All diagnostic serologic testing for celiac disease should be performed before a gluten-free diet is initiated. Table 4 summarizes the sensitivity, specificity, and positive and negative predictive values of serologic tests for untreated celiac disease. High titers of tTG are an accurate marker for CD and eliminate the need for biopsy.¹
• CBC, ferritin level: Iron deficiency anemia (microcytic anemia, low ferritin level) may be present.
• Celiac disease can lead to malabsorption: Screen for vitamin B₁₂ level, folate level, vitamin D level, serum calcium, albumin, magnesium; vitamin B₁₂ deficiency, vitamin D deficiency, hypomagnesemia, and hypocalcemia are not uncommon in celiac disease.
• Biopsy of the small bowel, considered the gold standard, has been questioned as a reliable and conclusive test in all cases. It may be reasonable in children with significant elevations of tTG levels (>100 U) to first try a gluten-free diet and consider biopsy in those who do not improve with diet. Repeat small-bowel biopsies are no longer required to show healing when there is a clear response to a gluten-free diet.
• The HLA-DQ2 allele is identified in >90% of patients with celiac disease, and HLA-DQ8 is identified in most of the remaining patients. These genes occur in only 30% to 40% of the general population. Their greatest diagnostic value is in their negative predictive value, making them useful when negative in ruling out the disease.

• Consider bone density in newly diagnosed adult patients.
• Capsule endoscopy can be used to evaluate mucosa of the small intestine, especially if future innovations will allow mucosal biopsy.

Patients should be instructed on a gluten-free diet (avoidance of wheat, rye, and barley). Safe grains (gluten-free) include rice, corn, oats, buckwheat, millet, amaranth, quinoa, sorghum, and teff (an Ethiopian cereal grain). The lowest amount of daily gluten that causes damage to the celiac intestinal mucosa is 10 to 15 mg/day. One slice of bread contains 1.6 g of gluten. Principles of initial dietary therapy for patients with celiac disease are summarized in Box 2.

• Correct nutritional deficiencies with iron, folic acid, calcium, vitamin D, and vitamin B₁₂ as needed.
• Prednisone 20 to 60 mg qd gradually tapered is useful in refractory cases.
• Lifelong gluten-free diet is necessary. A referral to a nutritionist experienced in celiac disease and gluten-free diet is recommended at initial diagnosis.

• Prognosis is good with adherence to a gluten-free diet. Rapid improvement is usually seen within a few days of treatment. Healing of the intestinal damage typically occurs within 6 to 24 mo after initiation of the diet. Lack of response to gluten-free diet occurs in 5% of patients and is due to unintentional ingestion of gluten or presence of coexisting GI disorders such as inflammatory bowel disease (IBD), lactose or other carbohydrate intolerance, and pancreatic insufficiency.
• Serial antigliadin or antiendomysial antibody tests can be used to monitor the patient’s adherence to a gluten-free diet.
• Repeat small-bowel biopsy after treatment generally reveals significant improvement. It is also useful to evaluate for increased risk of small-bowel T-cell lymphoma in these patients, especially untreated patients. Some experts recommend a repeat biopsy only in selected patients who have an unsatisfactory response to a strict gluten-free diet; however, recent data (Lebwohl et al) show that the risk for lymphoproliferative malignancy (LPM) is affected by the results of follow-up intestinal biopsy performed to document mucosal healing. Increased risk for LPM in CD is associated with the follow-up biopsy results, with a higher risk among patients with persistent villous atrophy. Follow-up biopsy may effectively stratify patients with CD by risk for subsequent LPM.

• The presence of dermatitis herpetiformis is pathognomonic for celiac disease.
• In close relatives, repeated serum tTG IgA testing may be useful in those with positive HLA-DQ2 or HLA-DQ8 tests because celiac disease may not manifest until later in life, and initial negative results do not preclude the possibility of future onset of celiac disease.
• Celiac disease should be considered in patients with unexplained metabolic bone disease, osteoporosis, transaminasemia, or hypocalcemia, because gastrointestinal symptoms are absent or mild. Clinicians should also consider testing children and young adults for celiac disease if unexplained weight loss, abdominal pain or distention, or chronic diarrhea is present.
• Screening for celiac disease is recommended in first-degree relatives. It should also be considered in patients with type 1 diabetes mellitus and in those with certain autoimmune disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, IBD, thyroid disease (hypothyroidism occurs in up to 15% of patients with celiac disease), systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome due to increased risk of celiac disease in these populations. Screening persons with Down syndrome or Turner syndrome has also been recommended.
• The prevalence of celiac disease in patients with dyspepsia is twice that of the general population. Screening for celiac disease should be considered in all patients with persistent dyspepsia.
• Patients with celiac disease have an overall risk of cancer that is almost twice that of the general population. The risk of adenocarcinoma of the small intestine is increased manifold compared with the risk in the general population. Celiac disease is also associated with an increased risk for non-Hodgkin lymphoma, especially of T-cell type and primarily localized in the gut. Lymphoma is 4 to 40 times more common, and death from lymphoma is 11 to 70 times more common in patients with celiac disease. Patients with refractory celiac disease are at greatest risk for T-cell lymphoma.
• Patients with celiac disease who have followed a gluten-free diet for prolonged periods may not experience relapse of symptoms for several months after gluten is reintroduced.
• A preliminary trial of a transglutaminase 2 inhibitor (ZED1227) has revealed attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.²

Celiac Disease (Patient Information)

Dermatitis Herpetiformis (Related Key Topic)

Malabsorption (Related Key Topic)