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Celiac Disease

Synonyms: Cœliac Disease, Celiac Sprue, Nontropical Sprue, Gluten-Sensitive Enteropathy

, MS, PhD, CGC, , MD, MS, , MS, CGC, and , MD.

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Initial Posting: ; Last Update: September 17, 2015.

Summary

Clinical characteristics.

Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, weight loss, abdominal pain, anorexia, lactose intolerance, abdominal distention, and irritability) and/or highly variable non-gastrointestinal findings (iron deficiency anemia, dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms.

Diagnosis/testing.

The diagnosis of celiac disease relies on characteristic histologic findings on small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet. Most individuals with celiac disease have celiac disease-associated antibodies; for celiac disease to develop, specific allelic variants of the human leukocyte antigen (HLA) class II genes HLA-DQA1 and HLA-DQB1 must be present. Because 30% of the general population has one or more of the celiac disease-associated alleles and only 3% of these individuals develop celiac disease, presence of celiac disease-associated HLA alleles is not diagnostic of celiac disease; however, their absence essentially excludes the diagnosis.

Management.

Treatment of manifestations: Lifelong adherence to a strict gluten-free diet (avoidance of wheat, rye, and barley); treatment of nutritional deficiencies (iron, zinc, calcium, fat-soluble vitamins, folic acid); standard treatment of osteoporosis.

Prevention of primary manifestations: Lifelong gluten-free diet.

Surveillance: For symptomatic individuals responsive to a gluten-free diet, periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations; repeat small-bowel biopsy one to three years following diagnosis. For symptomatic individuals unresponsive to a gluten-free diet, periodic evaluation for refractory celiac disease, ulcerative enteritis, T-cell lymphoma, and other gastrointestinal cancers.

Agents/circumstances to avoid: Dietary gluten.

Evaluation of relatives at risk: Molecular genetic testing of first-degree relatives of a proband (including young children) to monitor those with known celiac disease-susceptibility alleles for early evidence of celiac disease in order to institute gluten-free diet early in the disease course.

Genetic counseling.

Celiac disease is a multifactorial disorder resulting from the interaction of HLA-DQA1 and HLA-DQB1 allelic variants known to be associated with celiac disease susceptibility, less well-recognized variants in non-HLA genes, gliadin (a subcomponent of gluten), and other environmental factors. Some empiric risk data for at-risk relatives are available.

Diagnosis

The definitive diagnosis of celiac disease is made by identification of characteristic histologic changes on biopsy of the duodenum (Table 1) during upper gastrointestinal endoscopy while the patient maintains a gluten-containing diet [Lebwohl et al 2012].

Indications for duodenal biopsy include the following:

Other approaches to diagnosis have been proposed:

  • Recent guidelines published by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition [Husby et al 2012] allow the diagnosis of celiac disease to be made in the absence of a duodenal biopsy in the following select circumstance: a symptomatic child with a highly elevated TTG IgA (>10x the upper limit of normal), a second blood sample showing an elevated endomysial antibody, and an HLA haplotype consistent with celiac disease (DQ2 or DQ8). These new guidelines recognize the reality that in these high-probability circumstances, parents may wish their child to avoid the upper endoscopy.
    Note: These guidelines have been met with some controversy and at present no guidelines in the United States recommend a biopsy-free diagnosis of celiac disease.
  • The “four out of five rule” (suggested by Catassi & Fasano [2010] and described in Sapone et al [2012]) proposes that the diagnosis of celiac disease can be made if four of the five following characteristics are present:

    1. Typical symptoms of celiac disease
    2. High-titer elevated celiac disease antibodies
    3. A compatible HLA haplotype (DQ2 or DQ8)
    4. Enteropathy found on small bowel biopsy
    5. Response to a gluten-free diet

    The “four out of five rule” has not been officially endorsed by official guidelines, and at present the standard of care for the diagnosis of celiac disease includes a duodenal biopsy in all cases, with the possible exception of symptomatic children as specified by European guidelines.

Additional overviews of celiac disease diagnosis are provided by Hill & Rakitt [2014] and Guandalini & Assiri [2014]. Ten key recommendations for diagnosis and management are summarized in Oxentenko & Murray [2015].

Testing Strategies for Establishing the Diagnosis of Celiac Disease

The testing strategies below are recommendations based on clinical practice of celiac disease centers and a review of the literature.

In a Symptomatic Individual prior to Beginning a Gluten-Free Diet

Note: For a description of symptoms see Clinical Characteristics.

Specific celiac disease-associated antibody testing. Celiac disease-associated antibody testing is reviewed in Leffler & Schuppan [2010]. The most useful single antibody test is tissue transglutaminase (tTG) IgA. The sensitivity and specificity of celiac serology testing is increased with the use of more than one antibody test. It is important to test total IgA at the same time as celiac disease-associated antibody testing to rule out IgA deficiency.

  • Tissue transglutaminase (tTG) IgA. Measurement of serum concentration of tissue transglutaminase (tTG) immunoglobulin A (IgA) is often recommended for initial testing because of its high sensitivity and specificity for celiac disease, relatively low cost, and ease of test performance and reliability [Leffler & Schuppan 2010]. This antibody against an intestinal protein develops as a result of the celiac disease autoimmune process.
  • Anti-deamidated gliadin-related peptide (a-DGP) antibodies IgA and IgG. This test detects antibodies binding synthetic deamidated gliadin-related peptides (DGPs). In preliminary studies examining groups with a high prevalence of celiac disease, both isotypes (IgA and IgG) were shown to be highly sensitive and specific for active celiac disease [Vermeersch et al 2010]. An increase in DGP antibody levels may precede an increase in serum concentration of tTG-IgA in young children [Liu et al 2007]. However, as in all antibody tests, a minority of individuals have false negative results.
  • Endomysial antibody (EMA) IgA. Serum concentration of EMA IgA has the highest specificity (~99%) but is more expensive and more time-consuming to perform and is potentially more prone to false negative results than serum concentration of tTG IgA. Because it is determined by indirect immunofluorescence, serum concentration of EMA IgA is subject to observer variability, which affects its sensitivity. When performed in an experienced laboratory, this test has a higher specificity (approaching 100%) than tTG antibody testing and is useful in individuals with cirrhosis.
  • Measurement of serum concentration of total IgA to evaluate for selective IgA deficiency. The prevalence of selective IgA deficiency, a condition of unknown cause, is 1:700 in the general population. For unknown reasons the prevalence of selective IgA deficiency is higher (1:50) in individuals with celiac disease than in the general population.

    Because individuals with selective IgA deficiency do not produce IgA antibodies, the celiac-associated IgA antibodies tTG IgA and EMA IgA are not present in these individuals. Therefore, in these individuals, testing for celiac-associated IgG antibodies (tTG IgG or DGP-IgG) should be performed instead.

Note that first-generation antibodies to gliadin (AGA) are no longer recommended due to their relatively poor specificity. IgG antibodies to TTG and DGP should be measured in the case of selective IgA deficiency. Positive or equivocal results should be followed up by small-bowel biopsy.

If the clinical suspicion for celiac disease is strong or frank malabsorption is present, a small-bowel biopsy should be performed irrespective of the results of specific celiac disease-associated antibody testing.

Small bowel biopsy. Characteristic histologic findings that are the gold standard for the diagnosis of celiac disease include partial or complete villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (IELs). Based on the dynamic development of the pattern of the intestinal lesions and the frequency of mild lesions in celiac disease, Marsh [1992] proposed a four-stage grading classification to establish the diagnosis and to assess improvement in response to a gluten-free diet (Table 1).

Although these changes are not unique to celiac disease, reversion of intestinal damage after gluten withdrawal is unique to celiac disease.

The positive predictive nature of the biopsies depends on the relative prevalence of celiac disease as compared to other causes of enteropathy in the population.

Table 1.

Classification of Intestinal Lesions in Celiac Disease

TypeMucosal Findings
Stage 0. Preinfiltrative stageNormal
Stage 1. Infiltrative lesion 1Increased intraepithelial lymphocytes
Stage 2. Hyperplastic lesionStage 1 changes plus hyperplastic crypts
Stage 3. Destructive lesion 2Stage 2 changes plus:
  • Partial villous atrophy (termed 3a)
  • Subtotal villous atrophy (3b)
  • Total villous atrophy (3c)
Stage 4. Hypoplastic lesion 3Total villous atrophy with crypt hypoplasia
1.

Stage 1 can also be the result of other disease processes such as inflammatory bowel disease (IBD), use of nonsteroidal anti-inflammatory drugs (NSAIDs), Sjögren syndrome, helicobacter pylori gastritis, and possibly other food intolerances.

2.

Stage 3, the classic lesion of celiac disease and the most common biopsy finding, can be seen with other conditions including tropical sprue, small-bowel bacterial overgrowth, use of NSAIDS, acute gastroenteritis, and self-limited enteritis.

3.

Stage 4 is occasionally seen in elderly individuals.

Small-bowel biopsy can fail to detect histologic changes of celiac disease in the following circumstances:

  • Gluten-free diet
  • Early stages of the disease
  • Patchy mucosal lesions
  • Masking of celiac effect by peptic changes
  • Insufficient number of samples taken
  • Incorrect orientation of the slide during microscopic analysis
  • Latent celiac disease (defined as a positive celiac-associated antibody screen, but no villous atrophy on small-bowel biopsy) [Alaedini & Green 2005, Hill et al 2005]

False positive interpretations of celiac disease also occur as a result of over-interpretation of poorly oriented biopsies.

Guidelines recommend four to six duodenal biopsies for evaluation of celiac disease due to the patchy nature of histopathologic features in this disease [Green & Cellier 2007, Lebwohl et al 2011]. Adherence to these guidelines is low in the United States and efforts to increase submission of the recommended number of biopsies are warranted [Lebwohl et al 2011].

  • When celiac disease-associated antibodies are absent, molecular genetic testing for celiac disease-associated HLA alleles can assist in excluding or determining susceptibility to celiac disease if suspicion for the disease remains. (See In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing.)
  • A definitive diagnosis of celiac disease is made in the presence of a small-bowel biopsy showing characteristic histologic changes and clinical and/or histologic improvement on a gluten-free diet; however, exceptions include individuals with self-limited enteritis and tropical sprue who improve on a gluten-free diet.
  • For individuals with no detectable celiac disease-associated HLA alleles on molecular genetic testing, examination for alternative causes of symptoms is necessary (see Differential Diagnosis).

In a Symptomatic Individual who is on a Gluten-Free Diet

Celiac-specific antibody testing is not useful for individuals on a gluten-free diet since these antibodies are usually no longer present. If exploring the diagnosis of celiac disease is desired, the individual can undergo a gluten challenge (consisting of a gluten-containing diet for at least two weeks) prior to celiac serology and a small-bowel biopsy to confirm the diagnosis.

If the individual does not wish to pursue a gluten challenge because of the risk of illness and intestinal damage, a definitive diagnosis of celiac disease is not possible. The individual foregoes establishing the diagnosis with certainty and continues the gluten-free diet if it is alleviating symptoms. In this case, molecular genetic testing can provide information about susceptibility to celiac disease.

Molecular genetic testing for celiac disease-associated HLA alleles can exclude the diagnosis of celiac disease when absent and can determine the susceptibility to celiac disease when present.

For celiac disease to be able to develop, specific variants of the human leukocyte antigen (HLA) class II genes HLA-DQA1 and HLA-DQB1 must be present. These two genes together encode the alpha and beta chains of the celiac-associated heterodimer proteins DQ2 and DQ8 [Sollid 2002; reviewed in Guandalini et al 2014] (see Figure 1).

Figure 1. . Formation of DQ2 and DQ8 A.

Figure 1.

Formation of DQ2 and DQ8 A. The DQ2 molecule, consisting of the α-chain protein encoded by the HLA-DQA1*0501 allele and the β-chain protein encoded by the HLA-DQB1*0201 allele on the same parental chromosome (i.e., in cis configuration). (more...)

Using any of a variety of test methods, the HLA-DQA1 and HLA-DQB1 genotypes can be determined to detect the presence or absence of the celiac disease-associated alleles. Individuals are predisposed to celiac disease if they have any of the following results:

  • DQ2-positive (HLA-DQA1*0501 or *0505 and HLA-DQB1*0201 or *0202)
  • Half DQ2-positive (HLA-DQA1*0501 or 0505 or HLA-DQB1*0201 or 0202)
  • DQ8-positive (HLA-DQA1*03 and HLA-DQB1*0302)

The presence of these HLA alleles is necessary but not sufficient to cause celiac disease.

  • DQ2 is found in more than 90% of individuals with celiac disease and in 20%-30% of the general population [Sollid & Lie 2005].
  • A small percentage of individuals with celiac disease have either an HLA-DQA1 sequence variant (*0501 or *0505) or an HLA-DQB1 sequence variant (*0201 or *0202), but not both (i.e., only half of the DQ2 heterodimer).
  • DQ8 is found in 5%-10% of individuals with celiac disease and approximately 10% of the general population [Sollid & Lie 2005].

Interpretation of molecular genetic test results. Because 30% of the general population has one of the celiac disease-associated HLA alleles (encoding the heterodimers DQ2 and/or DQ8), and only 3% of individuals with one or both of these heterodimers develop celiac disease, identification of celiac disease-associated HLA alleles is not diagnostic of celiac disease.

Note: Unlike antibody testing and small-bowel biopsy, for which test reliability depends on the presence of gluten in the diet, the results of molecular genetic testing for celiac disease-associated HLA alleles can be interpreted accurately independently of diet [Alaedini & Green 2005].

  • Estimation of the degree of genetic risk for celiac disease associated with specific HLA-DQ2/DQ8 genotypes is possible (Table 3).
    Note: The actual risk for celiac disease may be significantly higher than shown in Table 3 in the presence of other factors, such as symptoms of celiac disease, positive results from celiac antibody tests, positive intestinal biopsy, and/or family members with celiac disease.
  • Absence of any celiac disease-associated HLA alleles (see Table 3) essentially excludes a diagnosis of celiac disease [Sollid & Lie 2005].

Table 3.

Genetic Risk from HLA-DQ2 and/or DQ8 Genotype Results

HLA DQ2/DQ8 Genotype 1Risk 1
DQ2+DQ81:7 (14.3%)
DQ2+DQ2 OR DQ2 Homozygous DQB1*021:10 (10%)
DQ8+DQ8 21:12 (8.4%) 2
DQ8+DQB1*021:24 (4.2%)
Homozygous DQB1*021:26 (3.8%)
DQ2 alone1:35 (2.9%)
DQ8 alone1:89 (1.1%)
Population risk1:100 (1%)
½ DQ2: DQB1*021:210 (0.5%)
½ DQ2: DQA1*051:1842 (0.05%)
No HLA-DQA/DQB celiac susceptibility alleles1:2518 (<0.04%)
1.

From Megiorni et al [2009] for all genotypes included except DQ8+DQ8

2.

In a Symptomatic Individual with Borderline or Ambiguous Celiac-Associated Antibody Testing

The individual should be tested for the combination of tTG, EMA, DGPs IgA and IgG, and total IgA, if not done previously.

For individuals who continue to have borderline or ambiguous results on celiac disease-associated antibody testing, molecular genetic testing for celiac disease-associated HLA alleles is recommended to exclude or determine HLA susceptibility to celiac disease. (See In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing.)

Small-bowel biopsy is recommended for individuals with celiac disease-associated HLA alleles and a high degree of clinical suspicion who are well established on a gluten-containing diet (the equivalent of 2 slices of bread/day for ≥2 weeks).

A definitive diagnosis of celiac disease is made in a person with a positive small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet.

In a Symptomatic Individual with Borderline or Ambiguous Small-Bowel Biopsy Results

Pathologic slides should be reviewed by an expert gastrointestinal pathologist.

Molecular genetic testing for celiac disease-associated HLA alleles is also of value (see In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing). For individuals with celiac disease-associated HLA alleles, celiac disease-associated antibody testing (TTG and/or DGPs/EMA) should be repeated, followed by small-bowel biopsy if indicated.

For individuals with negative celiac disease-associated antibody testing (i.e., TTG or DGPs/EMA) with or without celiac disease-associated HLA alleles, investigation into other causes of symptoms is indicated (see Differential Diagnosis).

In a Symptomatic Individual who has not Responded to a Gluten-Free Diet

Note: Individuals who continue to have symptoms despite adherence to a gluten-free diet are unlikely to have celiac disease.

Review of the results of the original celiac disease-associated antibody testing (if completed) prior to initiation of the gluten-free diet and a review of the original biopsy (if completed) by an expert in gastrointestinal pathology to confirm a diagnosis of celiac disease is suggested. If results are negative or inconclusive, the following are recommended:

  • Molecular genetic testing for celiac disease-associated HLA alleles to determine HLA susceptibility to celiac disease (See In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing.)
  • Investigation into other causes for symptoms other than celiac disease (see Differential Diagnosis).
  • Consultation with an expert dietician to analyze the diet for hidden sources of gluten and to evaluate for lactose or fructose intolerance, which can contribute to poor clinical response to a gluten-free diet.

If Refractory Sprue is Suspected

The following are indicated:

  • Immunohistochemical studies to assess for abnormal IELs
  • Studies for clonal T-cell receptor (TCR) gene rearrangements
  • Assessment for T-cell lymphoma, if indicated (See also Types of Celiac Disease, Refractory sprue/celiac disease.)
  • Imaging studies for both benign and malignant complications

Scenarios in which the diagnosis and management in celiac disease are difficult, including refractory sprue, are reviewed in Hoffenberg et al [2014].

For Individuals with a Disorder known to be Associated with Celiac Disease

Note: Disorders include: Down syndrome, Turner syndrome, selective IgA deficiency, autoimmune disorders (insulin-dependent diabetes mellitus, Sjögren syndrome, thyroiditis). As reviewed in Guandalini [2004], these disorders are associated with a higher prevalence of celiac disease than that found in the general population (see Prevalence).

Celiac-specific antibody testing is recommended.

Molecular genetic testing for celiac disease-associated HLA alleles may be considered to rule out the diagnosis of celiac disease in those with no celiac disease-associated HLA alleles. (See In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing.)

For Women with Infertility

Because undiagnosed celiac disease is a risk factor for infertility [Lasa et al 2014], celiac-specific antibody testing may be considered for women with infertility in whom other etiologies have been ruled out. A gluten-free diet may have a positive effect on fertility in women with celiac disease.

Clinical Characteristics

For in-depth reviews of celiac disease and manifestations, see Green & Cellier [2007] and Guandalini & Assiri [2014].

Clinical Description

While previously considered primarily a gastrointestinal disorder of malabsorption, celiac disease is now known to be a systemic autoimmune disease with gastrointestinal symptoms and multiple, highly variable non-gastrointestinal symptoms (see Figure 2). It is induced by dietary gluten in genetically susceptible individuals.

Figure 2. . Presenting symptoms in celiac disease.

Figure 2.

Presenting symptoms in celiac disease. The presenting symptoms are the main symptoms or indications that led to a diagnosis of celiac disease. “Bone disease” refers to evaluation for low bone density. “Incidental” refers (more...)

The onset of celiac disease may occur at any age after weaning; for adults, the peak age of diagnosis is between ages 30 and 50 years.

The average time between the onset of symptoms and diagnosis is 11 years because of the wide range of nonspecific symptoms shared by other disorders, the highly variable age of onset of symptoms, and the lack of symptoms in certain individuals (i.e., silent celiac disease) [Stavropoulos et al 2001]. The range in time between symptom onset and diagnosis also varies with the degree of awareness of the disease and the patient’s clinical presentation.

The female-to-male ratio of diagnosed celiac disease is reported to be 3:1.

Manifestations of Celiac Disease

Celiac disease is characterized by a wide range of manifestations and a high degree of variability between patients. See Figure 2 for a representation of the proportion of some key presentations.

Phenotypic features of celiac disease include but are not limited to the following:

  • Gastrointestinal manifestations. Chronic or recurrent diarrhea, malabsorption, abdominal pain and distention, bloating, vomiting, and weight loss. Patients often receive the diagnostic label of irritable bowel syndrome (IBS) [Hill et al 2005]. As many as 50% of individuals with celiac disease do not have daily diarrhea at the time of diagnosis [Rampertab et al 2006]. Additionally, many are overweight, even obese [Murray et al 2004].
  • Non-gastrointestinal manifestations. Dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, neurologic symptoms, and various secondary autoimmune disorders [Green & Jabri 2003, Hill et al 2005, NIH Consensus Committee 2005]

Types of Celiac Disease

Classic celiac disease refers to the presence of mild to severe symptoms of malabsorption such as diarrhea, failure to thrive, and weight loss [Hill et al 2005]. Children with classic celiac disease typically present with symptoms between ages six and 24 months [Fasano & Catassi 2005].

Non-classic celiac disease refers to celiac disease without prominent gastrointestinal symptoms or malabsorption (see Figure 2); however, individuals with atypical celiac disease can also have gastrointestinal symptoms such as reflux, abdominal pain, bloating, vomiting, constipation, and dyspepsia, which are often mislabeled IBS. Approximately 70% of patients are diagnosed based on extraintestinal manifestations associated with celiac disease.

Iron deficiency anemia is the most common presentation of non-classic celiac disease, and may be the only finding.

Dermatitis herpetiformis, an intensely pruritic rash on the extensor surfaces of the extremities, is a common non-gastrointestinal manifestation.

Other extraintestinal presentations include osteoporosis/osteopenia, dental enamel hypoplasia, infertility and/or recurrent fetal loss, vitamin deficiencies, elevated transaminases, fatigue, psychiatric syndromes, and various neurologic conditions, including peripheral neuropathy, ataxia, seizures, migraines, attention-deficit hyperactivity disorder (ADHD), and poor school performance.

Non-classic celiac disease usually presents in later childhood or adulthood. Children with non-classic celiac disease can present with unexplained short stature, neurologic symptoms, and delayed puberty.

Non-classic celiac disease is more common than classic celiac disease [Ludvigsson at al 2013].

Silent celiac disease. Silent celiac disease is defined as the lack of symptoms in the presence of a positive celiac-associated antibody screen and villous atrophy on small-bowel biopsy. Individuals with silent celiac disease are most often identified through an affected family member or through screening programs. (see Figure 3) [Fasano & Catassi 2005].

Figure 3. . The celiac iceberg represents all people who are genetically susceptible to celiac disease and have a positive celiac-associated antibody test result.

Figure 3.

The celiac iceberg represents all people who are genetically susceptible to celiac disease and have a positive celiac-associated antibody test result. The majority of these individuals have latent celiac disease. The “tip of the iceberg” (more...)

Potential celiac disease. Latent celiac disease is defined as a normal small-bowel biopsy in an individual with a positive celiac disease serology. A subset of such individuals subsequently develop villous atrophy if they continue to ingest gluten.

Refractory sprue/celiac disease (RCD). Refractory sprue or RCD refers to persistence of symptoms of frank malabsorption with persistent intestinal inflammation and villous atrophy despite a strict gluten-free diet for at least six to 12 months. All individuals with refractory sprue are older than age 20 years. Few studies of persons with well-characterized refractory sprue have been reported in the literature. The prognosis is uncertain, although some persons respond to corticosteroids and immunosuppressive agents:

  • Primary refractory sprue describes the condition in which individuals have never responded to a gluten-free diet. Molecular genetic testing is important in this group because the individuals lack a response to the gluten-free diet, which is one of the major diagnostic criteria.
  • Secondary refractory sprue refers to the condition in which individuals have a full recovery, followed later by a relapse, despite adherence to the gluten-free diet.

An alternate classification for RCD involves the determination of the intraepithelial lymphocytes (IELs) in persons with RCD:

  • In active, uncomplicated celiac disease the IELs have surface expression of CD3 and CD8, a normal occurrence. In addition, these lymphocytes are not clonally restricted (i.e., polyclonal).
  • In RCD1, the IELs are normal.
  • In RCD2, the IELs are abnormal in the following ways:
    • They have lost surface expression of CD3, CD8, and the TCR.
    • CD3 is detectable within the cell.
    • They have generally become clonal.

RCD2 has a worse outcome than RCD1 because of high mortality resulting from the poor response to immunosuppression and a high rate of progression to enteropathy-associated T cell lymphoma (EATL). The risk for EATL in persons with refractory sprue may exceed 50% [Green & Jabri 2003].

Genotype-Phenotype Correlations

See Table 3 for genetic risk from HLA-DQ2 and /or DQ8 genotype results.

The highest genetic risk is in individuals with both DQ2 and DQ8.

Among affected individuals, no difference in clinical severity of celiac disease is observed between those with the HLA-DQ2 genotype only and those with the HLA-DQ8 genotype only.

Individuals with DQ2 who are homozygous for the HLA-DQB1*02 allele are at higher risk for celiac disease than individuals with DQ2 and one HLA-DQB1*02 allele (Table 3).

Homozygosity for the HLA-DQB1*02 allele is reportedly found more frequently in individuals with classic celiac disease than in individuals with non-classic celiac disease and in complicated cases including refractory sprue and EATL [Karinen et al 2006].

It is possible for individuals who have half of the DQ2 molecule (i.e., only the HLA-DQA1 sequence variant [*0501 or *0505] or only the HLA-DQB1 sequence variant [*0201 or *0202]) to develop celiac disease, but the risk is much lower than for individuals who have the full HLA-DQ2 genotype (i.e., both the HLA-DQA1 sequence variant [*0501 or *0505] and the HLA-DQB1 sequence variant [*0201 or *0202]) [Zubillaga et al 2002, Margaritte-Jeannin et al 2004].

Penetrance

The penetrance of celiac disease is low. Of individuals with a celiac-associated HLA allele genotype, approximately 3% develop celiac disease. See Testing Strategies, In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing and Table 3. See Genetic Counseling for details regarding risk to family members.

Other genetic influences on penetrance of celiac disease in individuals with the HLA-DQ2 or HLA-DQ8 genotype clearly exist, as evidenced by clustering of celiac disease in families. The following differences are theorized to affect penetrance:

  • Intestinal permeability. Increased intestinal permeability has been observed in individuals with celiac disease compared to individuals without the disorder, possibly allowing entry of more gliadin peptides into the submucosa. Zonulin, a protein involved in tight junction regulation, is upregulated by gliadin in a sustained fashion in individuals with celiac disease, leading to increased paracellular permeability, whereas this effect is limited and transient in individuals without the disorder [Fasano 2011].
  • Innate immune response to gliadin. Genetic differences in the innate immune response to gliadin separate from the HLA-associated immune response appear to contribute to development of celiac disease and villous atrophy in some individuals.

Prevalence

Prevalence and epidemiology of celiac disease is reviewed in Guandalini et al [2014].

Once thought to be a rare condition, celiac disease is now known to affect approximately 1% of individuals in the US. However, a national survey in 2012 estimated that only 17% of individuals with celiac disease are diagnosed [Rubio-Tapia et al 2012]. Physician education about the variable clinical presentation and the use of celiac disease-associated antibody testing in diagnosis can increase the rate of diagnosis, as demonstrated in Ireland and Finland. In some regions of Finland up to 70% of the 1% of the general population predicted to have celiac disease have been diagnosed [Collin et al 2007].

In a US study, the overall prevalence of celiac disease in a group with no known risk factors was one in 133 (0.8%), compared to one in 22 in first-degree relatives of an index case, one in 39 in second-degree relatives, and one in 56 in individuals with either gastrointestinal symptoms or an extra-gastrointestinal disorder associated with celiac disease [Fasano et al 2003].

Using tTG IgA testing, Hoffenberg et al [2003] found that the prevalence of celiac disease in children age five years is one in 104 in the general population in Denver, Colorado.

Celiac disease is considered to be common in Europe, the US, Australia, Mexico, and some South American countries. It has also been reported in northwest India. The highest reported prevalence of celiac disease is 5.6%, found in a refugee population in North Africa.

Celiac disease is rarely diagnosed in individuals of sub-Saharan African descent, although African Caribbean and African American individuals with celiac disease have been reported. The rate of underdiagnosis in these and other minority groups may be high.

The prevalence of celiac disease is increased in the following disorders [Fasano et al 2003, Hoffenberg et al 2003, Treem 2004, Green 2005, NIH Consensus Committee 2005]:

  • Down syndrome (prevalence of celiac disease: 5%-12%)
  • Turner syndrome (~3%)
  • Selective IgA deficiency (~2%-10%)
  • Autoimmune disorders including:
    • Insulin-dependent diabetes mellitus (~6%)
    • Sjögren syndrome (~5%)
    • Thyroiditis (~2%-4%)

The prevalence of refractory sprue is not known; it is probably quite rare.

Differential Diagnosis

Celiac disease is underdiagnosed because of its variable, often subtle, presentations and clinical overlap with several other conditions.

Conditions that tend to mask or divert a diagnosis of celiac disease include dyspepsia, IBS, inflammatory bowel disease (IBD), tropical sprue, constipation, chronic fatigue, and various neurologic syndromes [Alaedini & Green 2005, NIH Consensus Committee 2005]. Some of these conditions can occur in conjunction with celiac disease.

It is estimated that 36% of individuals diagnosed with celiac disease initially had the diagnosis of IBS [Stavropoulos et al 2001]. Approximately 5% of individuals with IBS and 2% of persons with IBD also have celiac disease [Sanders et al 2001, Yang et al 2005].

Causes of gluten sensitivity other than celiac disease. It is increasingly evident that the number of individuals who turn to a gluten-free diet and benefit from it is much higher than the projected number of persons with celiac disease. In the consensus on new nomenclature and classification of gluten-related disorders (reviewed by Sapone et al [2012]), the three classes of gluten-related disorders as determined by pathogenic mechanism are:

  • Autoimmune (celiac disease, dermatitis herpetiformis, and gluten ataxia);
  • Allergic (wheat allergy); and
  • Immune-mediated, but not autoimmune or allergic (non-celiac, non-allergic gluten sensitivity).

Wheat allergy, an adverse immunologic (allergic) reaction to proteins in wheat, is characterized by production of anti-wheat IgE antibodies. Varieties of wheat allergy are:

  • Classic food allergy;
  • Wheat-dependent, exercise-induced anaphylaxis (WDEIA);
  • Occupational asthma (baker’s asthma) and rhinitis; and
  • Contact urticaria.

A review of wheat allergy is provided by Levy & Levy-Carrick [2014].

Skin prick tests, in vitro IgE assays, and oral food challenges are diagnostic approaches for wheat allergy.

Wheat and/or gluten allergy has been reported to have a prevalence of 0.4% in the US.

Non-celiac, non-allergic gluten sensitivity, which is distinct from celiac disease, also involves gluten sensitivity that improves on a gluten-free diet. Individuals who have non-celiac gluten sensitivity have intolerance to gluten, but do not have histologic findings of celiac disease (e.g., characteristic findings on intestinal biopsy) or elevated levels of celiac-specific antibodies (e.g., tTG or EMA IgA) [Sapone et al 2012, Catassi et al 2014]. Although some may have elevated anti-native gliadin IgA antibodies (AGA), no diagnostic markers are specific for non-celiac, non-allergic gluten sensitivity. The condition is defined by improvement on a gluten-free diet and exclusion of celiac disease and wheat allergy.

Non-celiac gluten sensitivity can present with intestinal symptoms (including IBS) and extraintestinal symptoms similar to those of celiac disease [Sapone et al 2011]. Individuals with neurologic or gastrointestinal symptoms in the absence of celiac disease who report improvement with a gluten-free diet are difficult to evaluate and may receive a diagnostic label of “gluten sensitivity” or “gluten intolerance.”

The pathologic responses to gluten in celiac disease and non-celiac gluten sensitivity are different: Celiac disease is caused by an adaptive immune response, while non-celiac gluten sensitivity is thought to be caused by an innate immune response [Sapone et al 2011].

It has been estimated that for every one person who is diagnosed with celiac disease there are six to seven individuals with non-celiac gluten sensitivity.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with celiac disease, the following evaluations are recommended:

  • Small-bowel biopsy in those who are well established on a gluten-containing diet to assess the degree of villous atrophy (Table 1). However, the degree of villous atrophy does not correlate with the severity of the clinical findings.
  • Baseline bone-density test in adults to evaluate for osteoporosis/osteopenia. In those with osteoporosis, vitamin D and parathyroid hormone concentrations should be evaluated [Green & Jabri 2003].
  • Screening tests for anemia, abnormal liver function, and nutrient deficiencies (iron, calcium, vitamin D, vitamin B12, folic acid)
  • Evaluation for a coexisting malignancy or autoimmune disease in symptomatic and/or elderly individuals [Alaedini & Green 2005, Pietzak 2005]

Treatment of Manifestations

Celiac disease. Ideally, the care of a newly diagnosed individual should be provided by a team including a gastroenterologist, primary care physician, and experienced nutritionist (see Figure 4). Local branches of national support groups can be helpful as additional resources [NIH Consensus Committee 2005] (see Figure 4).

Figure 4.

Figure 4.

An approach to the management of newly diagnosed celiac disease [Pietzak 2005] With permission from MM Pietzak, MD

The only treatment for individuals with celiac disease is strict adherence to a gluten-free diet that requires lifelong avoidance of wheat, rye, and barley:

  • Treatment with a gluten-free diet should be started only after the diagnosis has been established by intestinal biopsy.
  • A dietitian experienced in treating celiac disease should be involved.
  • In approximately 70% of affected individuals, symptoms improve within two weeks after starting a gluten-free diet.
  • For some patients, even a small amount of gluten (i.e., 100 mg) can damage the small intestine. Note that a slice of bread contains approximately 2.5 grams of gluten.
  • It can be difficult to adhere to the gluten-free diet, as gluten is found in many foods and other ingested products. Some hidden sources of gluten:
    • Non-starchy foods such as soy sauce and beer
    • Non-food items such as some medications, and cosmetics (e.g., lipstick)
  • Nutritional deficiencies and metabolic bone disease should be treated in the usual manner.

‘Unresponsive celiac disease’ refers celiac disease in patients who show no improvement on a gluten-free diet:

  • The most common reason for unresponsive celiac disease is the presence of small amounts of gluten in the diet. This gluten ingestion may be intentional, such as “cheating” at social events or using communion wafers, or unintentional, including ingestion of gluten in medications and gluten-containing foods in restaurants. Advice from a nutritionist experienced in management of the gluten-free diet is recommended to achieve the best results.
  • Assessment for lactose or fructose intolerance is important, as these conditions can be responsible for lack of response to the gluten-free diet [Green & Jabri 2003].
  • Assessment for alternative or additional diagnoses such as microscopic colitis, pancreatic exocrine insufficiency, IBS, small intestinal bacterial overgrowth, and eating disorders is necessary in those in whom gluten contamination is not the explanation.

For individuals who are not responding to a gluten-free diet, identification of a celiac disease-susceptibility HLA haplotype can provide motivation to continue the diet, to examine the diet for hidden sources of gluten, to address the possibility of refractory sprue, or even to dismiss the previous diagnosis of celiac disease.

Refractory sprue or celiac disease. Individuals with persistent symptoms and intestinal inflammation despite adherence to a gluten-free diet may need to be treated with systemic corticosteroids (e.g., local-active budesonide) and immunosuppressants [Green & Jabri 2003, NIH Consensus Committee 2005].

Prevention of Primary Manifestations

See Treatment of Manifestations.

Breast-feeding had been thought to exert a protective effect against the development of celiac disease in early childhood; however, this was not shown to be the case in two recent clinical trials [Lionetti et al 2014, Vriezinga et al 2014].

Earlier studies comparing breast-fed children with children who were not breast-fed found that breast-fed children who then developed celiac disease were more likely to have:

  • A later age of onset of symptoms;
  • Fewer classic symptoms such as diarrhea, growth disturbance, vomiting, abdominal pain, or distention [Ivarsson et al 2002];
  • A higher rate of “non-classic” symptoms [D'Amico et al 2005].

Prevention of Secondary Complications

Treatment with a gluten-free diet can:

  • Reverse growth failure and the reduced bone mineralization in children with celiac disease;
  • Decrease the rate of spontaneous abortions and frequency of low-birth-weight infants in women with celiac disease;
  • Reduce to the general population level the risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin's lymphoma;
  • Reduce the excess risk of mortality in symptomatic individuals.

Surveillance

For individuals with celiac disease, abnormal celiac disease serologies should be followed to normalization, which usually occurs within six to 12 months of starting a strict gluten-free diet.

Follow-up biopsy can be considered to confirm healing of intestinal villi. Because some patients on a strict gluten-free diet can heal gradually, this should typically be done at least two years after the initial diagnosis.

For asymptomatic relatives who have the HLA-DQ2 or HLA-DQ8 celiac disease-susceptibility haplotype on molecular genetic testing and negative antibody results, tTG IgA testing should be performed at three- to five-year intervals to screen for the development of celiac disease-associated antibodies [Hill et al 2005, NIH Consensus Committee 2005, Pietzak 2005].

Agents/Circumstances to Avoid

Gluten in the diet (see Treatment of Manifestations and Prevention of Primary Manifestations).

Evaluation of Relatives at Risk

Molecular genetic testing of first-degree relatives of individuals with celiac disease can identify those who are susceptible to developing celiac disease and who would benefit from serologic testing to screen for celiac disease or silent celiac disease. Of note, first-degree relatives do not need to be symptomatic to consider molecular genetic testing. (See Testing Strategies, In a Symptomatic Individual who is on a Gluten-Free Diet, Molecular genetic testing.)

Early diagnosis of celiac disease and treatment with a gluten-free diet can prevent secondary complications.

  • Individuals who do not have the celiac disease-associated HLA alleles DQ2 and DQ8 do not need to undergo serologic screening for celiac disease.
  • Individuals who have celiac disease-associated HLA alleles (Table 3) are followed by celiac disease-associated antibody testing at three- to five-year intervals.
    • Small-bowel biopsy is recommended when celiac disease-associated antibody testing is positive.
    • A definitive diagnosis of celiac disease is made in a person with a positive small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Click here (pdf) for information on therapies under investigation for treatment of celiac disease.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

HLA-DQ2 genotype-related celiac disease susceptibility is inherited in an autosomal dominant or autosomal recessive manner depending on the parental celiac disease-susceptibility HLA genotypes (see Figure 5A).

Figure 5. . Modes of inheritance of A.

Figure 5.

Modes of inheritance of A. DQ2-related celiac disease susceptibility and B. DQ8-related celiac disease susceptibility in families in which one parent has the respective celiac disease-susceptibility HLA haplotype and the other parent does not have the (more...)

HLA-DQ8 genotype-related celiac disease susceptibility is inherited in an autosomal dominant manner (see Figure 5B).

Risk to Family Members

For an individual whose HLA status is unknown and who has an affected first-degree relative, the risk of developing celiac disease is the range of 5% to 20% [Freeman 2010, Fasano et al 2003].

Parents of a proband

  • Empiric data suggest that the risk to parents of a proband of developing celiac disease is approximately 5%-10% [Fasano et al 2003, Treem 2004].
  • The risk to a parent of having celiac disease is increased when the parent is known to have the DQ2 heterodimer and/or the DQ8 heterodimer. The risk is less when only half of the DQ2 heterodimer (i.e., the HLA-DQA1 sequence variant or the HLA-DQB1 sequence variant, but not both) is present.
  • At least one parent of an individual with the DQ2 celiac disease-susceptibility HLA haplotype (see Figure 5A) or the DQ8 celiac disease-susceptibility HLA haplotype (see Figure 5B) has the same HLA haplotype as the proband.
  • Each parent of an individual who has DQ2 in the trans configuration (see Figure 5A) has at least one of the relevant HLA alleles.
  • Although nearly all individuals diagnosed with DQ2- or DQ8-related celiac disease susceptibility have a parent who has the DQ2 or the DQ8 heterodimer or half of the DQ2 heterodimer (i.e., the DQA1 sequence variant or the DQB1 sequence variant), the family history often appears to be negative because of reduced penetrance, failure to diagnose the disorder in family members, late onset of the disease in the affected parent, or early death of the parent before the onset of symptoms.

Sibs of a proband

  • The overall empiric risk for celiac disease in sibs of a proband is 7%-20% if the HLA haplotype is not known [Treem 2004, Bardella et al 2007, Freeman 2010]. If the HLA haplotype of the parents is known, the risk to the sibs can be refined.
  • Sibs who share the same celiac disease-susceptibility HLA haplotype with the proband are at a risk of developing celiac disease that approaches 40% [Treem 2004].
  • If a parent of the proband has the DQ2 celiac disease-susceptibility haplotype in cis configuration (see Figure 5A) or the DQ8 celiac disease-susceptibility HLA haplotype (see Figure 5B), the risk to each sib of inheriting the celiac disease-susceptibility HLA haplotype is 50%.
  • If one parent of the proband has half of the DQ2 heterodimer (HLA-DQA1*0501 or *0505) and the other parent has half of the DQ2 heterodimer (HLA-DQB1*0201 or *0202), the risks to sibs are as follows:
    • Risk of inheriting both HLA haplotypes and having the full DQ2 heterodimer encoded in trans configuration: 25%
    • Risk of inheriting half of the DQ2 heterodimer (HLA-DQA1*0501 or *0505) or (HLA-DQB1*0201 or *0202): 50%
    • Risk of inheriting neither the HLA-DQA1*0501 or *0505 nor the HLA-DQB1*0201 or *0202 celiac disease-susceptibility haplotype: 25%

Offspring of a proband

  • The overall risk for celiac disease in offspring of a proband is 5%-10% if the celiac disease-susceptibility HLA result is not known. The risk increases when the offspring has the DQ2 celiac disease-susceptibility HLA haplotype and/or the DQ8 celiac disease-susceptibility HLA haplotype [Treem 2004]. The risk is lower when only half of the DQ2 heterodimer (i.e., the DQA1 sequence variant or the DQB1 sequence variant, but not both) is present.
  • Each child of an individual with the DQ2 celiac disease-susceptibility HLA haplotype (see Figure 5A) or the DQ8 celiac disease-susceptibility HLA haplotype (see Figure 5B) has a 50% chance of inheriting a celiac disease-susceptibility HLA haplotype. Children who inherit the same HLA haplotype as the parent are at lower risk than sibs of a proband with the same HLA haplotype (i.e., <40%) [Treem 2004].
  • The child of a proband who has the DQ2 celiac disease-susceptibility HLA haplotype in the trans configuration (see Figure 5A) will inherit one of the celiac disease-susceptibility HLA haplotypes from the affected parent. Because the DQ2 or DQ8 heterodimer is found in 30%-40% of the general population, testing of the proband’s reproductive partner is appropriate.

Other family members of a proband

  • The risk to other family members depends on the DQ2 or DQ8 status of the proband's parents.
  • The celiac disease-susceptibility HLA status of the proband’s reproductive partner is also important as the DQ2 or DQ8 heterodimer is found in 30%-40% of the general population.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

While technically possible, prenatal testing of celiac disease-susceptibility HLA variants is not relevant in this complex disorder because:

  • The genetic change is common in the general population;
  • The genetic change is predisposing to but not predictive of celiac disease;
  • A highly effective treatment is available.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Celiac Disease Foundation (CDF)
    13251 Ventura Boulevard
    #1
    Studio City CA 91604
    Phone: 818-990-2354
    Fax: 818-990-2379
    Email: cdf@celiac.org
  • Celiac Sprue Association (CSA)
    PO Box 31700
    Omaha NE 68131-0700
    Phone: 877-272-4272 (toll-free); 402-558-0600
    Email: celiacs@csaceliacs.org
  • Medline Plus
  • My46 Trait Profile
  • National Foundation for Celiac Awareness (NFCA)
    PO Box 544
    Ambler PA 19002-0544
    Phone: 215-325-1306
    Email: info@celiacawareness.org
  • Gluten Intolerance Group of North America
    31214 124th Avenue Southeast
    Auburn WA 98092
    Phone: 253-833-6655
    Fax: 253-833-6675
    Email: info@gluten.net; admin@gluten.net

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Celiac Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Celiac Disease (View All in OMIM)

146880MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DQ ALPHA-1; HLA-DQA1
212750CELIAC DISEASE, SUSCEPTIBILITY TO, 1; CELIAC1
604305MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DQ BETA-1; HLA-DQB1

Molecular Genetic Pathogenesis

Celiac disease is a multifactorial disorder caused by an immune-mediated response to gliadin (a subcomponent of gluten) in genetically susceptible individuals leading to inflammation of the small bowel, villous damage, and resultant malabsorption. The HLA-DQA1 and HLA-DQB1 allelic variants known to be associated with celiac disease susceptibility are necessary but not sufficient to cause the disease. The etiology of many of the extraintestinal manifestations has not been fully elucidated. Other genes (many involved in the immune system or in intestinal permeability) and environmental factors are involved.

Click here (pdf) for information on other loci associated with celiac disease.

The Immunologic Mechanisms of Celiac Disease

When working properly, inflammatory mechanisms and immunologic responses in the digestive system provide protection from bacteria, toxins, and other foreign elements in the food and water supply. IgA, made in abundance by the intestinal immune system, is important in local (mucosal) immunity. In celiac disease, inappropriate immune responses lead to chronic inflammation and damage. The two main categories of immune response involved in celiac disease are: the adaptive immune response (HLA-specific) and the innate immune response (independent of HLA type).

Adaptive Immune Response (HLA-Specific): the Role of DQ2 and DQ8

Tissue transglutaminase (tTG), an enzyme found in every tissue of the body, protects the body through wound healing and bone growth. In the intestine, tTG deamidates gliadin, which introduces negative charges to the gluten peptides. Both DQ2 and DQ8, proteins on the surface of antigen-presenting cells (APCs) in the lamina propria, preferentially bind these negatively charged deamidated gluten peptides (see Figure 6 and Figure 7). Gluten-reactive T-helper cells (positive for the surface marker CD4) become activated on recognition of deamidated gluten peptides bound to DQ2 or DQ8 on APCs and produce cytokines including interferon gamma (IFN-γ). The ensuing inflammatory response results in the release of additional cytokines and chemicals leading to villous damage and atrophy. In response to inflammation, plasma cells in the inflamed intestinal tissue release antibodies, including anti-gliadin and anti-endomysial antibodies, and the autoimmune antibody against tTG (see Figure 7) [Treem 2004, Alaedini & Green 2005, Sollid & Lie 2005].

Figure 6. . Gluten-reactive CD4+ T-helper cells (with cell-surface CD4 markers) become activated upon recognition by a TCR of gluten peptides presented by HLA-DQ2 or HLA-DQ8 protein molecules on the surface of APCs in the lamina propria.

Figure 6.

Gluten-reactive CD4+ T-helper cells (with cell-surface CD4 markers) become activated upon recognition by a TCR of gluten peptides presented by HLA-DQ2 or HLA-DQ8 protein molecules on the surface of APCs in the lamina propria. Modified and expanded from (more...)

Figure 7. . The celiac small intestinal lesion showing both adaptive and innate immune mechanisms.

Figure 7.

The celiac small intestinal lesion showing both adaptive and innate immune mechanisms. A. Gluten peptides are transported across the epithelial barrier and are deamidated by tissue transglutaminase (tTG). CD4+ T cells in the lamina propria recognize the (more...)

Celiac disease is strongly associated with the class II HLA protein molecules DQ2 and DQ8, encoded by alleles at the HLA-DQA1 and HLA-DQB1 loci. These HLA-DQ sequence variants are the single most important genetic influence in celiac disease susceptibility, with the remainder of disease susceptibility attributed to unknown sequence variants in non-HLA genes. The great majority (>90%) of individuals with celiac disease are DQ2-positive, and most of the remainder are DQ8-positive. A small percentage have half of the DQ2 molecule. DQ2 and DQ8 confer susceptibility to celiac disease by presenting the gliadin subcomponent of gluten to specific CD4+ T-helper cells of the immune system in the intestinal mucosa (see Figure 6 and Figure 7) [Sollid 2002, Sollid & Lie 2005].

Allelic Variants Involved in Making the DQ2 and DQ8 Protein Molecules

The HLA-DQ2 and -DQ8 proteins are heterodimers found on the surface of antigen-presenting cells (APCs). DQ2 and DQ8 proteins are each made up of an α chain and a β chain encoded by specific sequence variants of the HLA-DQA1 and HLA-DQB1 genes, respectively.

Individuals with celiac disease who have DQ2:

  • Have the DR17-DQ2 celiac disease-susceptibility haplotype [HLA-DRB1*0301;HLA-DQA1*0501;HLA-DQB1*0201]
    OR
  • Are heterozygous for the celiac disease-susceptibility haplotypes DR11 or DR12-DQ7 [HLA-DRB1*11/12;HLA-DQA1*0505;DQB1*0301] or DR7-DQ2 [HLA-DRB1*07;HLA-DQA1*0201;HLA-DQB1*0202]

Individuals with celiac disease who have DQ8 have the DR4-DQ8 celiac disease-susceptibility haplotype (HLA-DRB1*04; HLA-DQA1*03;HLA-DQB1*0302) [Sollid & Lie 2005] (see Figure 1).

Innate Immune Response

In addition to the adaptive immune mechanism involving CD4+ T-helper cells described in Figure 6, an innate response involving intraepithelial CD8+ cytotoxic T lymphocytes (IELs) plays a role in the pathogenesis of celiac disease. In individuals with celiac disease, gluten independently induces epithelial stress through overproduction of interleukin-15 cytokine (IL-15) from IELs. The stress molecules MIC and HLA-E are also induced; they upregulate the expression of activating NK receptors (e.g., NKG2D) on the surface of CD8+ T cells, conferring NK-like properties to the T cells, which then attack intestinal epithelial cells indiscriminately, leading to intestinal damage [Hüe et al 2004, Jabri et al 2005] (see Figure 7).

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Suggested Reading

  • Fasano A. Clinical Guide to Gluten-Related Disorders. NASPGHAN Foundation. Philadelphia, PA: Lippincott Williams &Wilkins; 2014.
  • Green PH, Jones R. Celiac Disease: A Hidden Epidemic. HarperCollins Publishers; 2006.

Chapter Notes

Acknowledgments

We would like to acknowledge genetic counselor Katie Storm, MS, for her contribution to revisions.

We would also like to thank Dr. Ludvig Sollid for sharing his knowledge and insight.

Author History

Peter HR Green, MD (2008-present)
Benjamin Lebwohl, MD, MS (2015-present)
Cara L Snyder, MS, CGC (2008-present)
Annette K Taylor, MS, PhD, CGC (2008-present)
Danielle O Young, MS, CGC; Kimball Genetics, Inc (2008-2015)

Revision History

  • 17 September 2015 (me) Comprehensive update posted live
  • 3 July 2008 (me) Review posted live
  • 28 September 2006 (cs) Original submission
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