Reference [1,2,3,4,5,6]
Risk factor Comment
Female sex
  • The prevalence in women is 2 - 3 times higher than that in men
First-degree relative with disease
  • The disease is prevalent in 10 - 15% of people who have a first-degree relative with the disease
Type 1 diabetes
  • Celiac disease is present in 3 - 16% of patients with type 1 diabetes
HLA DQ2 and HLA-DQ8 haplotypes
  • The HLA-DQ2 haplotype (alleles A1*05 and B1*02) is present in 90% of patients with celiac disease
  • One of two HLA-DQ2 alleles (A1*05 or B1*02) is present in 5% of patients
  • The HLA-DQ8 haplotype is present in 5% of patients with celiac disease
  • See labs below for more
IgA deficiency
  • IgA deficiency is present in 2 - 3% of patients with celiac disease
  • IgA deficiency may affect laboratory diagnosis of celiac disease
  • See labs below 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
  • Some studies have suggested that the introduction of gluten between 4 - 6 months of age may decrease the risk, while introducing gluten before 4 months and after 7 months may increase the risk
  • Recent randomized trials have evaluated this hypothesis and found no effect - see studies for more
Rotavirus
  • In some observational studies, rotavirus infection in infancy has been associated with an increased risk of celiac disease
Breastfeeding
  • In some observational studies, the introduction of gluten while breastfeeding has been associated with a lower risk of celiac disease
  • A recent randomized controlled trial did not confirm this finding - see studies for more
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
  • Celiac disease is present in up to 5% of patients with Down's syndrome
Turner's syndrome
  • Celiac disease is present in up to 3% of patients with Turner's syndrome









Reference [7]
Presenting symptom/sign % 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%


Presenting symptom/sign % 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%




Antibody tests
Tissue transglutaminase
IgA antibodies (TTG IgA)
  • Sensitivity: > 95%; Specificity: > 95%
  • TTG IgA is the preferred screening test in adults. In children < 2 years old, TTG Abs are less sensitive, therefore a combination of TTG IgA + DGP (IgA and IgG) is the preferred screening method.
  • IgA deficiency is more common in patients with celiac disease (2 - 3%), so if suspicion for celiac disease is high, total IgA levels should also be drawn
  • Gluten-free diet - TTG IgA levels will return to normal in patients consuming a gluten-free diet. Weakly positive patients may return to normal within weeks of starting a gluten-free diet. After 6 - 12 months, 80% of patients will have normal levels. By 5 years, > 90% of patients will have normal levels. TTG IgA levels may also be used to monitor compliance with a gluten-free diet.
Tissue transglutaminase
IgG antibodies (TTG IgG)
  • Sensitivity: widely variable; Specificity: 86 - 100%
  • TTG IgG are useful in patients who have suspected IgA deficiency. The sensitivity and specificity of TTG IgG is highly variable, therefore it is not as accurate as TTG IgA.
  • Gluten-free diet - TTG IgG levels will return to normal in patients consuming a gluten-free diet. Weakly positive patients may return to normal within weeks of starting a gluten-free diet. After 6 - 12 months, 80% of patients will have normal levels. By 5 years, > 90% of patients will have normal levels.
Deamidated gliadin peptide IgA and IgG antibodies
(DGP Abs)
  • Sensitivity (IgG): > 90%; Specificity (IgG): > 90%
  • DGP IgG antibody is useful in patients who have suspected IgA deficiency
  • When screening children younger than 2 years of age for celiac disease, TTG IgA + DGP (IgA and IgG) are the recommended screening tests
  • Gluten-free diet - DPG Ab levels (IgG and IgA) will return to normal in patients consuming a gluten-free diet. Weakly positive patients may return to normal within weeks of starting a gluten-free diet. After 6 - 12 months, 80% of patients will have normal levels. By 5 years, > 90% of patients will have normal levels. DGP Ab levels may also be used to monitor compliance with a gluten-free diet.
Endomysial IgA antibody
  • Sensitivity: > 90%; Specificity: 98%
  • Endomysial antibodies are antibodies to the connective tissue inside muscle. TTG IgA antibody is the target antigen for endomysial antibodies.
  • Endomysial IgA antibodies are highly specific (low false-positives) but less sensitive than other tests. The test is also expensive and typically only recommended when there is concern over a possible false-positive TTG Ab test.
  • Endomysial IgG antibody tests are not widely available
Other
  • Anti-gliadin antibodies are antibodies to native gliadin (undeamidated). This test is no longer recommended because newer tests are more sensitive.
  • Anti-reticulin antibodies are antibodies to reticulin, a connective tissue. This test is no longer recommended because newer tests are more sensitive.
Genotype
HLA DQ2/DQ8 genotype
  • The HLA-DQ2 haplotype (alleles A1*05 and B1*02) is present in 90% of patients with celiac disease, and one of two HLA-DQ2 alleles (A1*05 or B1*02) is present in 5% of patients. The HLA-DQ8 haplotype is present in the remaining 5% of patients with celiac disease.
  • This means a person who tests negative for both HLA-DQ2 and HLA-DQ8 is very unlikely to have celiac disease with a negative predictive value of > 99%
  • The HLA-DQ2 haplotype is present in 25 - 30% of the general population, therefore a positive test has little meaning in screening situations

    • The American College of Gastroenterology states that haplotype testing may be useful in the following situations:
      • Equivocal small-bowel histological finding (Marsh I-II) in seronegative patients
      • Evaluation of patients on a gluten-free diet in whom no testing for celiac disease was done before gluten-free diet
      • Patients with discrepant celiac-specific serology and histology
      • Patients with suspicion of refractory celiac disease where the original diagnosis of celiac remains in question
      • Patients with Down's syndrome






Reference [1,2,3]
Other conditions with celiac-like symptoms
Disease Comment
Irritable bowel syndrome (IBS)
  • Many patients with celiac disease are initially diagnosed with IBS
Non-celiac gluten sensitivity
  • Diagnosis of exclusion
  • Condition where patients have symptoms of celiac disease when they consume gluten, but they do not meet the serologic or histopathologic criteria for celiac disease
Wheat allergy
  • May be diagnosed with skin prick tests or blood tests
Lactose intolerance
  • May be diagnosed with dietary challenge/removal or lactose breath hydrogen test
Pancreatic insufficiency
  • Often difficult to diagnose
  • Pancreatic calcifications may be seen on radiographs


Reference [1,3]
Potential causes of duodenal villous atrophy
Disease Comment
Tropical sprue
  • Tropical sprue is a chronic diarrheal disease of unknown etiology that occurs in tropical regions along the equator
Small bowel bacterial overgrowth
  • A condition marked by overgrowth of non-native bacteria in the small bowel
  • Typically occurs in the setting of bowel abnormalities (structural, decreased motility, etc.)
Autoimmune enteropathy
  • Rare disease caused by autoantibodies to enterocytes
Drug-induced enteropathy
Whipple disease
  • Syndrome of chronic diarrhea, joint pain, and malabsorption caused by T. whipplei infection
Collagenous sprue
  • Rare disease marked by excessive subepithelial collagen deposition in the small bowel
Crohn's disease
Eosinophilic enteritis
  • Disease is marked by eosinophilic infiltration into the stomach and duodenum
Intestinal lymphoma
  • Intestinal lymphoma may cause villous atrophy
  • Celiac disease increases the risk of enteropathy-associated T-cell lymphoma, but the disease is still very rare among celiac patients (see cancers below)
Intestinal tuberculosis
  • Although rare, tuberculosis may infect the gastrointestinal tract
Infectious enteritis
Graft vs host disease
AIDS enteropathy
  • Syndrome of chronic diarrhea and wasting in AIDS patients
  • Infectious and neoplastic causes should be ruled out before making diagnosis












Reference [1,3]
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%




Study Criteria Intervention Primary outcome Results
Gluten
vs
placebo
at 4-6 months of age
to prevent celiac disease


NEJM
2014


PubMed abstract
Inclusion criteria:
  • Full-term infants 0 - 3 months of age
  • Positive for HLA-DQ2, HLA-DQ8, or HLA-DQB1*02 heterodimer
  • At least one first-degree relative with biopsy-confirmed celiac disease

Exclusion criteria:
  • Down's syndrome
  • Turner's syndrome
Group 1 (475 patients) - 200 mg of vital wheat gluten mixed with 1.8 g of lactose daily for 8 weeks starting at 16 weeks of age

Group 2 (469 patients) - placebo (2 g of lactose) daily for 8 weeks starting at 16 weeks of age

  • Participants were considered to have adhered to the intervention assignment if at least 75% of the study material (gluten or placebo) was ingested and no additional gluten was consumed
  • After the intervention, parents were advised to introduce gluten gradually, using regular products and standardized recommendations
The primary outcome was the frequency of celiac disease at 3 years of age. The diagnosis of celiac disease was based on the histologic findings of small-bowel biopsies, according to the 1990 criteria of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Primary outcome
  • Group 1 - 5.9%
  • Group 2 - 4.5%
  • Gluten vs placebo HR 1.23, 95%CI [0.79 - 1.91]

Other
  • Breastfeeding (either exclusive or ongoing during gluten introduction) did not have a significant effect on outcomes
  • The incidence of celiac antibodies was not significantly different between groups

Study Criteria Intervention Primary outcome Results
Gluten introduction
at 6 or 12 months
of age to prevent celiac disease


NEJM
2014


PubMed abstract
Inclusion criteria:
  • Newborns with at least one first-degree relative with celiac disease

Patient characteristics
  • First-degree relative(s) with celiac disease:
    one - 91%, two - 8%; three - 1%
  • Standard risk HLA - 89%; High risk HLA - 11%
Group A (297 patients) - introduction of gluten-containing foods (pasta, semolina, and biscuits) at 6 months of age

Group B (256 patients) - introduction of gluten-containing foods at 12 months of age

  • At 12 months of age, all children began to receive a normal diet containing gluten
The primary outcome was the prevalence of celiac disease autoimmunity (celiac antibodies) and of overt celiac disease among patients with a standard-risk or high-risk HLA genotype according to trial group at 5 years of age. Overt celiac disease was defined as celiac disease autoimmunity and a Marsh classification of 2 or 3 at small-bowel biopsy (on a scale of 0 to 3, with higher scores indicating villous atrophy). Primary outcome at 5 years of age

Celiac autoimmunity
  • Group A - 21%
  • Group B - 20%
  • p=0.59 for between group comparison

Overt celiac disease
  • Group A - 16%
  • Group B - 16%
  • p=0.78 for between group comparison