- ACRONYMS AND DEFINITIONS
- ACG - American College of Gastroenterology
- DGP - Deamidated gliadin peptide
- HLA - Human leukocyte antigen
- RCT - Randomized controlled trial
- TTG - Tissue transglutaminase
- ULN - Uppper limit of normal
- PREVALENCE
- About 1% of the world's population is affected by celiac disease, and it occurs anywhere wheat, barley, or rye is consumed. Because of its nonspecific and sometimes mild symptoms, celiac disease is often missed, with up to 79% of cases being undiagnosed in screening studies. The frequency of diagnosis is increasing, however, as celiac disease awareness has grown. [2,3]
- RISK FACTORS
- Female sex
- Women are affected 2 - 3 times more than men
- First-degree relative with disease
- 10 - 15% of people with celiac have a first-degree relative with the disease
- Type one diabetes
- 3 - 16% of type one diabetics have celiac disease
- HLA-DQ2 and HLA-DQ8 haplotypes
- The HLA-DQ2 haplotype (alleles A1*05 and B1*02) is present in 90% of celiac patients, and one allele (A1*05 or B1*02) is present in 5%. The HLA-DQ8 haplotype is found in the remaining 5%. See celiac labs for more.
- IgA deficiency
- IgA deficiency is present in 2 - 3% of patients with celiac disease, and IgA levels should be checked if IgA antibodies are used for screening. See celiac labs for more.
- Timing of gluten introduction into the diet
- Observational studies have found that the timing of gluten introduction into the diet is associated with celiac disease, with introduction between 4 - 6 months reducing the risk and introduction before 4 months and after 7 months increasing the risk. Randomized controlled trials examining this effect have had mixed results. (see celiac prevention studies).
- Rotavirus
- In some observational studies, rotavirus infection in infancy has been associated with an increased risk of celiac disease
- Other autoimmune disease
- Celiac disease is more prevalent in patients with other autoimmune diseases (e.g. Hashimoto's thyroiditis, Sjögren's, autoimmune liver disease, IgA nephropathy, peripheral neuropathy)
- Down's syndrome
- Up to 5% of Down's syndrome patients have celiac disease
- Turner's syndrome
- Up to 3% of Turner's syndrome patients have celiac disease [1,2,3,4,5,6]
- PATHOLOGY
- Overview
- Celiac disease is caused by an abnormal immune response to gluten peptides in the upper small intestine. Gluten is found in wheat, barley, and rye, and when it reaches the small intestine, it breaks down into gliadin. In celiac disease, gliadin is able to pass through the epithelial barrier in the small intestine and reach the underlying lamina propria. The cause of epithelial gliadin permeability is uncertain but may be due to an underlying pathological process (e.g. infection) or alterations in tight intercellular junctions.
- Once gliadin reaches the lamina propria, it is deamidated by tissue transglutaminase (TTG). Deamidated gliadin then reacts with HLA-DQ2 or HLA-DQ8 receptors on antigen-presenting cells that stimulate T- and B-cell activation, leading to cytokine release, antibody production, and lymphocyte infiltration. Over time, inflammation causes villous atrophy and crypt hyperplasia in epithelial cells. [3,4]
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- NATURAL COURSE
- Overview
- Celiac disease may develop in childhood or adulthood, and its natural course is highly variable. The pathology progresses through the sequence of events listed below, and the interval between each step may be weeks to years, depending on the individual.
- The presence of gluten-related antibodies does not always lead to celiac disease. In one study, 49% of high-risk children with tissue transglutaminase antibodies converted to negative antibodies over time despite continued gluten exposure.
- Sequence of events in the development of celiac disease
- 1. Gluten exposure
- 2. Development of gluten-related antibodies
- 3. Duodenal villous atrophy, crypt hyperplasia, and lymphocyte infiltration
- 4. Symptoms of celiac disease [2,9]
- SYMPTOMS
- Children
- Classic symptoms of celiac disease in infants and young children include diarrhea, abdominal distention, and failure to thrive. Advances in serologic screening and heightened awareness have increased disease recognition, and a broader array of symptoms have now been identified. [3]
- Presenting symptoms in 263 children (≤ 16 years) diagnosed with celiac disease in New Zealand are shown in the table below
Celiac disease in children | |
---|---|
Presenting symptom | % of patients |
Abdominal pain | 44% |
Diarrhea | 33% |
Iron-deficiency anemia | 32% |
Poor weight gain | 25% |
Bloating | 23% |
Nausea and vomiting | 16% |
Asymptomatic (found during screening) |
14% |
Lethargy | 14% |
Weight loss | 10% |
Micronutrient deficiency (iron, folate, zinc, etc.) |
10% |
Constipation | 6% |
Poor health/recurrent infections | 5% |
Short stature | 4% |
Irritability | 4% |
Headaches | 2% |
Puberty delay | 1% |
Poor sleep | 1% |
- Adults
- Classic symptoms of celiac disease in adults include chronic diarrhea, abdominal distention, steatorrhea, postprandial abdominal pain, bloating, and weight loss. [1]
- Results from a study that looked at the presenting symptoms in 172 patients (> 16 years) diagnosed with celiac disease in the U.S. are presented in the table below. The average age in the study was 42 years, and the average duration of symptoms before diagnosis was 4 years.
Celiac disease in adults | |
---|---|
Presenting symptom | % of patients |
Diarrhea | 37% |
Other✝ | 26% |
Anemia | 13% |
Screening (affected family member) |
12% |
Bone disease | 8% |
Childhood celiac disease | 8% |
Malignancy | 5% |
Incidental diagnosis (found during EGD for other condition) |
5% |
- WHOM TO TEST
- The ACG recommends testing the following patients for celiac disease:
- Patients with symptoms, signs, or laboratory evidence suggestive of malabsorption (e.g. chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain and bloating) should be tested for celiac disease
- Patients with symptoms, signs, or laboratory evidence for which celiac disease is a treatable cause should be considered for testing for celiac disease
- Patients with a first-degree family member who has a confirmed diagnosis of celiac disease should be tested if they show possible signs or symptoms or laboratory evidence of celiac disease
- Consider testing of asymptomatic relatives with a first-degree family member who has a confirmed diagnosis of celiac disease
- Celiac disease should be sought among the explanations for elevated serum aminotransferase levels when no other etiology is found
- Patients with Type I diabetes should be tested for celiac disease if there are any digestive symptoms, or signs, or laboratory evidence suggestive of celiac disease [1]
- DIAGNOSIS
- ACG 2013 recommendations
- All testing should be done while patients are consuming a gluten-containing diet
- Positive serologic testing should be confirmed with duodenal biopsies
- Adults and children > 2 years: the preferred screening test is TTG IgA
- Children younger than 2 years: the preferred screening test is a combination of TTG IgA and DGP (IgG and IgA)
- High-probability patients: if suspicion for celiac disease is high, total IgA levels should be measured because IgA deficiency is present in 2 - 3% of celiac disease patients. An alternative approach is to include both IgA and IgG-based testing, such as DGP IgG. Intestinal biopsy should be pursued even if serologies are negative.
- Patients with low IgA or IgA deficiency: IgG-based testing (DGP IgG and TTP IgG) should be performed
- Genotype testing: see genotype testing
- Antibodies directed against native gliadin are not recommended for the primary detection of celiac disease
- Combining several tests for celiac disease in lieu of TTG IgA alone may marginally increase the sensitivity for celiac disease but reduces specificity and therefore is not recommended in low-risk populations [1]
ANTIBODY TESTS |
---|
Tissue transglutaminase IgA (TTG IgA) antibodies
|
Tissue transglutaminase IgG (TTG IgG) antibodies
|
Deamidated gliadin peptide IgA and IgG antibodies (DGP Abs)
|
Endomysial antibodies (IgA and IgG)
|
Other
|
GENOTYPE |
HLA DQ2/DQ8 genotype
|
- Endoscopy
- Patients with positive serologic celiac testing should have their diagnosis confirmed with endoscopy. High-probability patients with negative serology should also have endoscopy.
- Histopathological findings in celiac disease include the following:
- Villous atrophy
- Lymphocytic infiltration of the intestinal epithelium
- Crypt hyperplasia [1]
- DIFFERENTIAL DIAGNOSIS
OTHER CONDITIONS WITH CELIAC-LIKE SYMPTOMS | |
---|---|
Disease | Comment |
Irritable bowel syndrome (IBS) |
|
Non-celiac gluten sensitivity |
|
Wheat allergy |
|
Lactose intolerance |
|
Pancreatic insufficiency |
|
POTENTIAL CAUSES OF DUODENAL VILLOUS ATROPHY | |
---|---|
Disease | Comment |
Tropical sprue |
|
Small bowel bacterial overgrowth |
|
Autoimmune enteropathy |
|
Drug-induced enteropathy |
|
Whipple disease |
|
Collagenous sprue |
|
Crohn's disease |
|
Eosinophilic enteritis |
|
Intestinal lymphoma |
|
Intestinal tuberculosis |
|
Infectious enteritis | |
Graft vs host disease | |
AIDS enteropathy |
|
- TREATMENT
- The primary treatment of celiac disease is a gluten-free diet, which leads to symptom resolution after 6 - 12 months in most people
- Newly-diagnosed patients may need to be tested for nutritional deficiencies, including iron, folic acid, vitamin D, and vitamin B12
- Gluten is found in products that contain wheat, barley, or rye. Links to information from the Celiac Disease Foundation on gluten-containing foods are provided below.
- SEQUELAE
- Cancers
- Patients with celiac disease are at an increased risk of certain cancers; however, the overall risk of these cancers is still very low. A gluten-free diet appears to lower the risk.
- Cancers associated with celiac disease include:
- Adenocarcinoma of the small intestine
- Enteropathy-associated T-cell lymphoma - may present as recurrent celiac symptoms after a period of control on a gluten-free diet; difficult to treat; has poor prognosis
- B-cell and T-cell lymphomas
- Esophageal cancers [1,2,3]
- Osteoporosis
- Osteoporosis is more common in patients with celiac disease due to a number of factors, including decreased calcium and vitamin D absorption, secondary hyperparathyroidism, magnesium deficiency, increased inflammatory mediators, and hypogonadism
- High-risk patients should have periodic bone mineral density testing
- A gluten-free diet has been shown to improve bone mineral density [1,4]
- Iron-deficiency anemia
- Celiac disease may reduce iron absorption in the duodenum, leading to iron-deficiency anemia, which is a presenting symptom in up to 32% of children and 13% of adults [1]
- Infertility
- Women and men with celiac disease appear to have a higher risk of infertility. A gluten-free diet appears to lower the risk. [1,4]
- Hyposplenism
- Celiac disease is the most common cause of hyposplenism, with 33 - 76% of patients having some degree of hyposplenism in studies. A gluten-free diet can help restore spleen function if splenic tissue loss and atrophy have not occurred.
- Spleen atrophy is a poor prognostic indicator in patients with severe celiac disease
- See care of the hyposplenic patient for more [11]
- REFRACTORY DISEASE
- Overview
- Most patients with celiac disease have symptom resolution after 6 - 12 months of a gluten-free diet. However, up to 30% of patients do not respond, and these individuals should be referred to a dietician to ensure that they are consuming a strict gluten-free diet. Antibody testing (TTG IgA, DGP IgA and IgG) may also be appropriate to monitor compliance.
- Consider the following in non-responsive patients:
- Nonadherence to a strict gluten-free diet
- Inadvertent gluten ingestion
- Other food intolerances (lactose and fructose intolerance)
- Incorrect diagnosis (see other causes of villous atrophy above)
- Refractory disease (see below)
- Refractory disease types
- Refractory celiac disease is defined as persistent or recurrent symptoms and signs of malabsorption with small-intestinal villous atrophy despite a strict gluten-free diet for more than 12 months and in the absence of other disorders including overt lymphoma
- Refractory celiac disease is uncommon, occurring in 1 - 2% of celiac patients
- Refractory celiac disease can be divided into two different types
- Type 1 refractory celiac disease
- In the U.S., Type 1 is more common than Type 2
- Lymphocyte phenotype (CD3+CD8+) and infiltration into mucosa is similar to that seen in untreated celiac disease
- May be treated with steroids, immunosuppressants, and biologicals
- Type 2 refractory celiac disease
- CD3-positive intraepithelial T-cells exhibit an abnormal immunophenotype with lack of expression of normal cell surface differentiation markers such as CD8 (CD3+CD8-)
- T-cell receptor analyses may reveal oligoclonal T-cell expansion within the small-bowel mucosa
- Type 2 disease is less responsive to therapy, but may be treated with steroids, immunosuppressants, biologicals, and bone marrow transplant
- Malnutrition may be severe requiring total parenteral nutrition
- RIsk for enteropathy-associated T-cell lymphoma is increased
- Prognosis is poor with a 5-year survival of 44%
- STUDIES
- STUDY
- Design: Randomized controlled trial (N=1004 | length = 3 years) in infants from the general population in England and Wales
- Treatment: Early introduction of allergenic foods (peanut, sesame, hen's egg, cow's milk, cod fish, and wheat) at 4 months old vs Standard introduction of allergenic foods at 6 months old
- Primary outcome: Diagnosis of celiac disease at 3 years old by positive antitransglutaminase type 2 antibodies and evaluation by gastroenterologist
- Results:
- Primary outcome: Early - 0%, Standard - 1.4% (p=0.02)
- Findings: In this analysis of infants in the EAT Study, the introduction of gluten from age 4 months was associated with reduced CD prevalence. These results suggest that early high-dose consumption of gluten should be considered as a strategy to prevent CD in future studies.
- STUDY
- Design: Secondary analysis of a randomized placebo-controlled trial (N=944, length = 3 years) in infants 4 - 6 months of age who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease
- Treatment: Gluten 200 mg daily vs Placebo daily for 8 weeks starting at age 4 months. After the intervention, parents were advised to introduce gluten gradually.
- Primary outcome: Frequency of biopsy-confirmed celiac disease at 3 years of age
- Results:
- Primary outcome: Gluten group - 5.9%, Placebo group - 4.5%
- Findings: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children.
- STUDY
- Design: Randomized controlled trial (N=832, length = 5 years) in newborns who had a first-degree relative with celiac disease
- Treatment: Introduction of gluten-containing foods (pasta, semolina, and biscuits) at 6 months of age vs 12 months of age. At 12 months of age, all children began to receive a normal diet containing gluten
- Primary outcome: Prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age
- Results:
- Celiac autoimmunity: 6-month group - 21%, 12-month group - 20%
- Overt celiac disease: 6-month group - 16%, 12-month group - 16%
- Findings: Neither the delayed introduction of gluten nor breastfeeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease.
- STUDY
- Design: Prospective cohort study (N=6605 | length = 5 years) in children carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease
- Exposure: Gluten intake during first 5 years of life
- Primary outcome: Celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples
- Results:
- Primary outcome: Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-gram/day increase in gluten consumption (HR 1.30 95%CI [1.22 - 1.38])
- Findings: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.
- BIBLIOGRAPHY
- 1 - PMID 23609613 - ACR 2013 GL
- 2 - PMID 23252527 - NEJM 2012 review
- 3 - PMID 17960014 - NEJM 2007 review
- 4 - PMID 12907013 - Lancet 2003 review
- 5 - PMID 25271603 - Early Gluten study 1
- 6 - PMID 25271602 - Early Gluten study 2
- 7 - PMID 26566488 - child presenting symptoms
- 8 - PMID 16564784 - adults presenting symptoms
- 9 - PMID 17573785 - ttg conversion in children
- 10 - PMID 21474172 - Post-splenectomy and hyposplenic states, Lancet (2011)