ACG clinical guidelines: diagnosis and management of celiac disease

Abstract

This guideline presents recommendations for the diagnosis and management of patients with celiac disease. Celiac disease is an immune-based reaction to dietary gluten (storage protein for wheat, barley, and rye) that primarily affects the small intestine in those with a genetic predisposition and resolves with exclusion of gluten from the diet. There has been a substantial increase in the prevalence of celiac disease over the last 50 years and an increase in the rate of diagnosis in the last 10 years. Celiac disease can present with many symptoms, including typical gastrointestinal symptoms (e.g., diarrhea, steatorrhea, weight loss, bloating, flatulence, abdominal pain) and also non-gastrointestinal abnormalities (e.g., abnormal liver function tests, iron deficiency anemia, bone disease, skin disorders, and many other protean manifestations). Indeed, many individuals with celiac disease may have no symptoms at all. Celiac disease is usually detected by serologic testing of celiac-specific antibodies. The diagnosis is confirmed by duodenal mucosal biopsies. Both serology and biopsy should be performed on a gluten-containing diet. The treatment for celiac disease is primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up. Non-responsive celiac disease occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms should lead to a review of the patient's original diagnosis to exclude alternative diagnoses, a review of the GFD to ensure there is no obvious gluten contamination, and serologic testing to confirm adherence with the GFD. In addition, evaluation for disorders associated with celiac disease that could cause persistent symptoms, such as microscopic colitis, pancreatic exocrine dysfunction, and complications of celiac disease, such as enteropathy-associated lymphoma or refractory celiac disease, should be entertained. Newer therapeutic modalities are being studied in clinical trials, but are not yet approved for use in practice. Given the incomplete response of many patients to a GFD-free diet as well as the difficulty of adherence to the GFD over the long term, development of new effective therapies for symptom control and reversal of inflammation and organ damage are needed. The prevalence of celiac disease is increasing worldwide and many patients with celiac disease remain undiagnosed, highlighting the need for improved strategies in the future for the optimal detection of patients.

Conflict of interest statement

Potential competing interests:

Dr. Rubio-Tapia has nothing to declare.

Dr. Hill serves on the editorial boards of Journal of Pediatrics and Journal of Pediatric Gastroenterology and Nutrition.

Dr. Kelly acts or has acted as a scientific and medical advisor to Alba, Alvine and ImmunosanT and has received research funding support on celiac disease from Alba and Shire.

Dr. Calderwood has nothing to declare.

Dr. Murray has received grant support from Alba Therapeutics (>$50,000), served on the Advisory Board of Alvine Pharmaceuticals, Inc. (<$10,000), and served as consultant to Ironwood, Inc. (<$10,000), Flamentera (<$10,000), Actogenix (<$10,000), Bayer Healthcare Pharmaceuticals (<$10,000), Vysera Biomedical (<$10,000), 2G Pharma, Inc. (<$10,000), ImmunosanT, Inc (<$10,000), and Shire US Inc (<$10,000).

Figures

Figure 1

Celiac disease diagnostic testing algorithm

Figure 2

An approach to gluten challenge for the diagnosis or exclusion of CD in patients maintained on a gluten free diet without prior definitive diagnostic testing. [Adapted from reference Leffler D, Gut 2012] 1. Tissue transglutaminase, endomysium and/or deamidated gliadin peptide antibody serology. 2. Normal or non-diagnostic histology in a patient with positive serology while maintaining a GFD requires gluten challenge and repeat biopsy for definitive diagnosis or exclusion of CD. 3. Those with positive celiac serology but a normal biopsy have potential CD and should be evaluated and monitored further depending upon their clinical circumstances 4. In one study of subjects receiving a gluten challenge for 14 days Marsh III histology was seen in 68%, positive celiac serology in 75% and either Marsh III histology or positive serology in 90%. Thus, a 2 week gluten challenge may yield false negative results in 10% of patients. The added diagnostic sensitivity of extending the challenge to 8 weeks is unknown. 5. Celiac serology antibody concentrations may continue to rise after a gluten challenge ends. In one study positive tTG serology was seen in 25% of subjects and positive DGP serology in 30% at the end of a 14 day gluten challenge; 50% had at least one positive serology on day 14. Positivity rates rose to 55% and 45% respectively 14 days later, despite the fact that subjects had resumed a GFD; 75% had at least one positive serology on day 28, 14 days after the gluten challenge ended.

Figure 3

An approach to monitoring CD [Adapted from Rubio-Tapia A. Seguimiento Médico del Paciente Celiaco. En Rodrigo L. editor. Enfermedad Celiaca. Barcelona, España. OmniaScience, 2012. In press] 1. TTG and DGP can be used for monitoring CD 2. Other tests may include complete blood count, ALT, vitamins (A, D, E, B12), copper, zinc, carotene, folic acid, ferritin, iron 3. Blood tests at follow-up should be individualized to verify correction of laboratory tests that were abnormal at baseline 4. The role of biopsy for monitoring CD is discussed in detail in the text

Figure 4

An approach to the investigation of NRCD and RCD. [Adapted from references Rubio-Tapia A Gut 2010 and Abdallah H Curr Gastroenterol Rep 2007] 1. Non-responsive celiac disease [NRCD] may be defined as persistent symptoms, signs or laboratory abnormalities typical of CD despite 6 to 12 months of dietary gluten avoidance. 2. Causes of non-celiac, small intestinal villous atrophy that may be misdiagnosed as CD include autoimmune enteropathy, tropical sprue, small intestinal bacterial overgrowth, hypogammaglobulinemia and combined variable immunodeficiency (CVID), collagenous sprue, eosinophilic enteritis, Crohn’s disease, and peptic duodenitis. 3. Conditions that present clinically in a similar fashion to CD but where villous atrophy is not evident include irritable bowel syndrome, food intolerances, small intestinal bacterial overgrowth, eosinophilic enteritis, Crohn’s disease, and microscopic colitis. 4. Positive celiac serologies despite 12 months of treatment with a GFD suggest that there may be ongoing gluten ingestion. 5. Refractory celiac disease (RCD) may be defined as persistent or recurrent malabsorptive symptoms and signs with small intestinal villous atrophy despite a strict GFD for more than 12 months and in the absence of other disorders including overt lymphoma. 6. Abnormal intestinal lymphocytes may be identified by immunohistochemistry of IELs or by flow cytometry showing an increased number of CD3 positive cells lacking CD8 or by the identification of clonal T-cell receptor gene rearrangement by molecular analysis.