Clinical characteristics.

Celiac disease is a common systemic autoimmune disease that can develop in genetically susceptible individuals as a response to dietary gluten. Celiac disease can be associated with gastrointestinal findings (e.g., diarrhea, malabsorption, abdominal pain and distention, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, iron deficiency anemia, osteoporosis/osteopenia, other nutrient deficiencies, migraines, chronic fatigue, epilepsy, depression, attention-deficit/hyperactivity disorder, joint pain/inflammation, infertility and/or recurrent fetal loss, delayed puberty, growth deficiency, dental enamel hypoplasia, abnormal liver function, autoimmune disorders, and increased risk of cancer). Classical celiac disease, characterized by prominent gastrointestinal symptoms, is less common than non-classical celiac disease, characterized by mild or absent gastrointestinal symptoms. Some individuals with celiac disease have no symptoms despite the presence of immune reactivity to gluten; these individuals are referred to as having silent celiac disease.

Diagnosis/testing.

The diagnosis of celiac disease is established in an individual with positive celiac serologic testing results while on a gluten-containing diet (tissue transglutaminase immunoglobulin [Ig] A, anti-deamidated gliadin-related peptide IgA and/or IgG, or endomysial antibody IgA) and characteristic histologic findings on small bowel biopsy.

Human leukocyte antigen (HLA) molecular genetic testing to detect celiac-associated HLA-DQA1 and HLA-DQB1 alleles is not necessary for initial diagnostic testing, but it is useful for diagnostic evaluation when serology or small biopsy results are inconclusive or discrepant. A negative result for celiac HLA genetic testing rules out celiac disease and a positive result identifies predisposition to celiac disease. Celiac HLA genetic testing is important for individuals who started a gluten-free diet before diagnostic evaluation.

Management.

Targeted therapy: Lifelong adherence to a strict gluten-free diet (avoidance of wheat, rye, and barley).

Treatment of manifestations: Nutrition assessment for those with persistent gastrointestinal manifestations despite removal of gluten from the diet; consider corticosteroids and immunosuppressants for refractory celiac disease; assess for malignancy in those with persistent poor weight gain and/or growth efficiency; consider dapsone for dermatitis herpetiformis; standard treatment for anemia if not responsive to gluten-free diet; standard treatment of osteoporosis; treatment of nutritional deficiencies (iron, zinc, calcium, fat-soluble vitamins, folic acid). Standard treatments for peripheral neuropathy, ataxia, seizures, migraines, poor school performance, psychiatric manifestations, joint pain and inflammation, fertility issues, pubertal delay, dental enamel hypoplasia, autoimmune disease, and cancer; evaluation for alternative causes of abnormal liver function if unresolved with gluten-free diet.

Surveillance: For symptomatic individuals responsive to a gluten-free diet, abnormal celiac disease serologies should be followed to normalization; physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations annually or as needed; measurement of hepatic profile and thyroid-stimulating hormone annually. Follow-up biopsy of intestinal villi can be considered for monitoring two years after diagnosis among individuals with a clinical and serologic response. Normalization of the intestinal biopsy is considered the aim of treatment with the diet.

Agents/circumstances to avoid: Dietary gluten.

Evaluation of relatives at risk: Celiac HLA genetic testing of first-degree relatives of a proband (including young children) for celiac-associated HLA-DQA1 and HLA-DQB1 alleles and determination of HLA-DQ status can be used to 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. Early diagnosis of celiac disease and treatment with a gluten-free diet can prevent secondary complications.

Genetic counseling.

Celiac disease is a complex multifactorial disorder. The risk to family members of a proband with celiac disease depends on their HLA genetic risk (i.e., their HLA-DQ status, the strongest determinant of celiac disease susceptibility), less well-recognized variants in non-HLA genes, exposure to dietary gluten, and the involvement of additional environmental influences. Empiric risk for celiac disease can be estimated based on HLA-DQ status and familial relationship to the proband.

Suggestive Findings

Celiac disease should be suspected in individuals with the following clinical and laboratory findings.

Clinical findings

• Gastrointestinal signs/symptoms (e.g., diarrhea, malabsorption, abdominal pain, distention, bloating, vomiting, weight loss), including signs/symptoms compatible with irritable bowel syndrome
• Dermatitis herpetiformis
• Chronic fatigue
• Joint pain/inflammation
• Neurologic manifestations (e.g., peripheral neuropathy, ataxia, seizures, migraines, attention-deficit/hyperactivity disorder, poor school performance)
• Osteoporosis/osteopenia
• Infertility and/or recurrent fetal loss
• Poor weight gain and/or growth deficiency
• Delayed puberty
• Dental enamel defects
• Individuals with disorders associated with celiac disease (e.g., Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, type 1 diabetes mellitus, Sjögren syndrome, thyroiditis)

Laboratory findings

• Iron deficiency anemia
• Vitamin and/or mineral deficiencies (e.g., calcium, vitamin D, vitamin B₁₂, folic acid, secondary hyperparathyroidism due to calcium and/or vitamin D deficiency)
• In individuals on a gluten-containing diet:
  • Elevated serum tissue transglutaminase (tTG) immunoglobulin (Ig) A
  • Elevated serum anti-deamidated gliadin-related peptide (DGP) IgA and/or IgG
  • Elevated serum endomysial antibody (EMA) IgA (highest specificity [~99%] but sensitivity subject to observer variability)
  • Note: Selective IgA deficiency is more prevalent in individuals with celiac disease (1:50) than in the general population. In individuals known to have IgA deficiency or with low total IgA results upon testing with tTG IgA, measurement of tTG IgG and DGP IgG should be performed [Rubio-Tapia et al 2023].

Establishing the Diagnosis

The diagnosis of celiac disease is established in an individual with:

• Positive celiac serologic testing while on a gluten-containing diet (elevated serum tTG IgA, serum DGP IgA and/or IgG, or EMA IgA);
  AND
• Characteristic histopathology of partial or complete villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes identified on four to six duodenal biopsies, while the individual maintains a gluten-containing diet or has resumed a gluten-containing diet for at least two weeks.

Diagnosis without a duodenal biopsy. Pediatric guidelines from Europe present a pathway for the diagnosis of celiac disease in children that does not include an intestinal biopsy. Under these guidelines a diagnosis of celiac disease could be considered in a child with a tTG IgA value of more than ten times the upper level of normal, positive celiac serologic testing on two occasions, and evaluation by a pediatric gastroenterologist [Husby et al 2020]. There is ongoing debate regarding this approach to diagnosis [Reilly et al 2018].

Role of celiac human leukocyte antigen (HLA) genetic testing. The presence of specific celiac-associated HLA-DQA1 and HLA-DQB1 allele(s) that encode the alpha and beta chains of the HLA-DQ heterodimers involved in the immune response to gluten (DQ2.5, DQ8, DQ2.2, and DQ7.5) is required for the development of celiac disease (see Determination of the HLA-DQ status and Figure 1). HLA genetic testing to detect these alleles is clinically indicated in the following:

Figure 1.

Human leukocyte antigen (HLA) association in celiac disease. Celiac-associated HLA-DQ heterodimers (molecules) are shown along with the relevant DR-DQ haplotypes and DQB1 and DQA1 alleles. The majority of individuals with celiac disease have the HLA-DQ2.5 (more...)

• Individuals who are already maintaining a long-term gluten-free diet at the time of initial evaluation. Celiac serology testing is not useful in these individuals.
• Individuals with conflicting serologic and histologic results (e.g., elevated serologies but a normal intestinal biopsy).
• Family members of affected individuals, to determine whether screening for active celiac disease is necessary or to rule out celiac disease and susceptibility in individuals with a negative result (absence of celiac-associated HLA alleles) [Rubio-Tapia et al 2023].

For overviews on HLA genetics and testing in celiac disease, see Brown et al [2019] and Megiorni & Pizzuti [2012].

Test methodologies. Celiac-associated HLA-DQA1 and HLA-DQB1 alleles may be detected by a variety of molecular genetic methodologies, most commonly polymerase chain reaction (PCR) and sequence-specific oligonucleotide probes or targeted genotyping by next-generation sequencing.

Determination of HLA-DQ status is based on detection of HLA-DQA1 and HLA-DQB1 celiac-associated alleles and their combinations [Sollid & Lundin 2014, Sciurti et al 2018, Brown et al 2019]. Celiac HLA reports may include a risk gradient based on the HLA genetic test results (see Penetrance, HLA genetic risk stratification).

The main HLA-DQ2 and HLA-DQ8 heterodimers (referred to as DQ2 and DQ8) or celiac-associated heterodimers with half of the DQ2 heterodimer are encoded by the specific HLA-DQA1 and HLA-DQB1 alleles (see Table 1).

The DQ2.5 heterodimer is the strongest determinant of celiac disease susceptibility and is present in >90% of individuals with celiac disease. DQ2.5 is encoded by DQB1*02 and DQA1*05 (hence 2.5). These alleles can be present on the same chromosome (in the DR3 haplotype, with DQB1*02:01 and DQA1*05:01 encoding the DQ2.5 heterodimer) or on opposite chromosomes (in the DR5/DR7 haplotypes, with DQB1*02:02 and DQA1*05:05 encoding the DQ2.5 heterodimer) [Megiorni & Pizzuti 2012, Sollid & Lundin 2014] (see Figure 1). The presence of alleles on the same chromosome is more common, with only 4% of individuals with HLA-DQ2.5 having alleles on opposite chromosomes [Gualandris et al 2021]. Although the "HLA-DQ2" is a serology designation focused on the beta chain, regarding celiac disease, "DQ2 positive" generally refers to the presence of DQ2.5.

DQ8 is encoded by DQB1*03:02 and DQA1*03 alleles as part of the DQ4-DQ8 haplotype [Megiorni & Pizzuti 2012, Sollid & Lundin 2014]. The predominant DQA1*03 allele in this haplotype is DQA1*03:01. DQ8 is present in ~5%-10% of individuals with celiac disease.

Of the remaining individuals with celiac disease without DQ2.5 or DQ8 (<5%) most have either DQ2.2 or DQ7.5 [Sollid & Lundin 2014]. DQ2.2 is encoded by DQA1*02:01 and DQB1*02:02 (thus including only the beta half of DQ2.5), and DQ7.5 is encoded by DQA1*05:05 and DQB1*03:01 (thus including only the alpha half of DQ2.5) [Sollid et al 2012]. "Half DQ2" has been used to refer to the presence of only the DQA1*05 or DQB1*02 components of DQ2.5.

See Figure 1 for diagrams of the celiac-associated DQ heterodimers (DQ2.5, DQ2.2, DQ7.5, and DQ8) along with depictions of the haplotypes of the HLA-DQA1 and HLA-DQB1 alleles with their linked HLA-DRB1 alleles.

An individual's celiac-associated HLA-DQA1 and HLA-DQB1 allele(s) in various combinations or alone determine the HLA genetic risk for celiac disease (see Table 2). This risk is based on how strongly the HLA-DQ status of the heterodimer is associated with celiac pathogenesis (e.g., how effectively the HLA-DQ heterodimer presents gluten peptides to CD4⁺ T cells and the robustness of the resulting T-cell inflammatory response). For example, DQ2.5 is strongly associated with celiac disease, while DQ2.2 is much less so, due to a structural difference between the heterodimers in the alpha chain (HLA-DQ2.5-Tyr22α vs HLA-DQ2.2-Phe22α) [Ting et al 2020]. Likewise, DQ8 confers a lower risk of celiac disease than DQ2.5 and has different binding characteristics to gluten peptides [Sollid & Lundin 2014, Levescot et al 2022].

Clinical Description

Celiac disease is a systemic autoimmune disease that can present as classical celiac disease with the presence of gastrointestinal manifestations resulting in malabsorption, non-classical celiac disease without prominent gastrointestinal manifestations or malabsorption, or silent celiac disease (see Figure 2). Non-classical celiac disease is more common than classical celiac disease [Ludvigsson at al 2013].

Figure 2.

Clinical phenotypes of adult celiac disease Adapted from Caio et al [2019]

Onset. Celiac disease is induced by dietary gluten in genetically susceptible individuals. The onset may occur at any age after introduction of gluten in the diet. Non-classical celiac disease usually presents in later childhood or adulthood. In 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 [Green et al 2001].

Gastrointestinal manifestations in those with classical celiac disease include chronic or recurrent diarrhea, malabsorption, poor weight gain, growth deficiency in childhood, abdominal pain and distention, bloating, vomiting, and weight loss in adults and children.

More than 50% of individuals (such as those with non-classical celiac disease) do not have daily diarrhea at the time of diagnosis [Rampertab et al 2006, Dominguez Castro et al 2017]. However, individuals with non-classical celiac disease can have some gastrointestinal symptoms such as reflux, abdominal pain, bloating, vomiting, constipation, and dyspepsia. Many individuals with non-classical celiac disease are overweight or obese [Murray et al 2004, Maleki et al 2024].

Non-gastrointestinal manifestations in individuals with both classical and non-classical celiac disease include the following:

• Dermatitis herpetiformis is common in celiac disease. It is an intensely pruritic rash most commonly found on the extensor surfaces of the extremities.
• Vitamin and mineral deficiencies. Iron deficiency anemia is a common presentation of non-classical celiac disease and may be the only finding. This may contribute to low bone density. Other common vitamin and mineral deficiencies include folic acid and vitamin B₁₂.
• Neurologic manifestations include migraines (the onset of which can be at any age), chronic fatigue, peripheral neuropathy, ataxia, and epilepsy (especially in childhood). Seizures may be accompanied by calcification in the brain; this is, however, extremely uncommon [Julian et al 2019].
• Psychiatric manifestations include depression and anxiety and attention-deficit/hyperactivity disorder.
• Joint pain/inflammation. Celiac disease is associated with an increased risk of rheumatoid arthritis and juvenile inflammatory arthritis [Doyle et al 2022]. Both peripheral and central arthropathy are found.
• Endocrine manifestations include infertility and/or recurrent fetal loss and delayed puberty. Children with non-classical celiac disease can present with unexplained short stature and delayed puberty.
• Dental enamel hypoplasia. This may be due to malabsorption of calcium or vitamin D but has also been associated with antibodies to ameloblast-specific proteins indicating autoimmunity as a central cause [Gruper et al 2023].
• Abnormal liver function. Abnormal liver function tests, most commonly elevated transaminases, are found in individuals with untreated celiac disease and usually normalize within one year of initiating a gluten-free diet. Autoimmune hepatitis is common [Haggård et al 2021]. Celiac disease may be a cause of cryptogenic cirrhosis [Yoosuf et al 2023].
• Autoimmune disease. The prevalence of autoimmune disease is increased in individuals with celiac disease including autoimmune thyroid disease [Roy et al 2016, Lebwohl et al 2018]. The risk of developing autoimmune disease may be modulated by treatment with a gluten-free diet [Golan et al 2022].
• Cancer. The risk of several malignancies is increased in individuals with celiac disease, including non-Hodgkin lymphoma (including enteropathy-associated T-cell lymphoma) and gastrointestinal cancers [Lebwohl et al 2022].

Potential celiac disease. Potential celiac disease is defined as a normal small bowel biopsy in an individual with positive celiac disease serology, regardless of the presence of symptoms. A subset of such individuals subsequently develop villous atrophy if they continue to ingest gluten; others may remain in this state or celiac serology testing may become negative. Only those with significant symptoms would be advised to start a gluten-free diet [Volta et al 2016].

Removal of gluten from the diet can result in:

• Improved growth;
• Increased bone mineralization in children with celiac disease;
• Decreased frequency of spontaneous abortions and low-birth-weight infants in women with celiac disease;
• Reduced risk for certain types of cancers including small-intestine adenocarcinoma, esophageal cancer, and non-Hodgkin lymphoma;
• Reduced risk of mortality in symptomatic individuals.

Refractory celiac disease (RCD) refers to persistence of clinical manifestations 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 RCD are older than age 20 years.

• Primary RCD refers to individuals who have never responded to a gluten-free diet.
• Secondary RCD refers to Individuals who have a full recovery followed later by a relapse despite adherence to a gluten-free diet.

An alternate classification for RCD involves the characterization 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 T-cell receptor.
  • CD3 is detectable within the cell.
  • They have generally become clonal.

RCD1 is considered to be relatively common. Individuals usually respond to corticosteroids (e.g., budesonide, prednisone).

RCD2 is rare. An international series demonstrated a 30% five-year mortality rate and prognostic factors that determined survival [Rubio-Tapia et al 2016]. Poor survival is typically due to a high rate of progression to enteropathy-associated T-cell lymphoma [Chander et al 2018].

Penetrance

The penetrance of celiac disease is low. Of individuals with celiac-associated HLA-DQA1 and HLA-DQB1 allele(s), approximately 3% develop celiac disease. This increases to 10%-20% or higher in first-degree relatives of an individual with celiac disease. The risk of developing celiac disease is affected by HLA-DQ status, determined by HLA-DQA1 and HLA-DQB1 genetic testing (see Table 2). Celiac disease heritability is 50%, while heritability from human leukocyte antigen (HLA) genetic variance is 40% [Sollid & Lundin 2014, Abadie et al 2024]. As noted in a review by Abadie et al [2024], concordance rates for celiac disease are 75% in monozygotic twins, 30% for HLA-identical sibs, and 10% for dizygotic twins [Abadie et al 2024]. There is a female predominance in celiac disease, as for many autoimmune disorders, with an approximately 2:1 ratio of females to males in children and adults with celiac disease [Sollid & Lundin 2014].

Dose effect of DQB1*02 allele. The dose of DQB1*02 has a strong effect on celiac risk. Individuals homozygous for a DQB1*02 allele have approximately fivefold the risk of celiac disease compared to heterozygotes [Liu et al 2014, Sallese et al 2020].

HLA genetic risk stratification. Genetic risk gradients for celiac disease according to celiac-associated HLA-DQA1 and HLA-DQB1 allele(s) have been reported (see Table 2). All risk gradients show a quantitative relationship between the type and proportion of DQ heterodimers, ranging from 1:7 for the highest risk to as low as 1:3,580 for no celiac-associated alleles. There are some differences between studies. A large US study of more than 10,000 individuals at risk for celiac disease found the highest risk (defined here as endomysial antibody [EMA] IgA positivity) was for individuals homozygous for DQ2.5 or individuals with DQ2.5 + DQ2.2 [Pietzak et al 2009]. A study of development of autoimmunity (tissue transglutaminase [tTG] antibodies) and celiac disease in individuals assessed from birth to age five years found that DQ2.5 homozygotes had the highest risk [Liu et al 2014]. It is biologically plausible that DQ2.5 homozygotes would have the highest risk, since DQ2.5 has stronger binding to gliadin and a more robust T-cell response than DQ2.2 or DQ8 [Sollid & Lundin 2014].

Nomenclature

HLA-DQA1 and HLA-DQB1 may also be referred to by the gene symbol alias CELIAC1 (see www.genenames.org).

Prevalence

Celiac disease affects approximately 1% of individuals in the United States and has been considered primarily a disease of individuals from European descent, but it is a worldwide condition with prevalence varying between countries and regions of countries [Sollid & Lundin 2014, Gatti et al 2024]. The highest reported prevalence of celiac disease is 5.6%, found in the Saharawi population in Algeria [Lionetti et al 2015]. The female-to-male ratio of diagnosed celiac disease is reported to be 2:1.

The incidence and prevalence of celiac disease is increasing globally. Newly diagnosed individuals have been increasing in the US and seven other countries studied in a large a meta-analysis, with a pooled average of 7.5% increase per year over the past several decades [King et al 2020]. The upward trend of prevalence has also been reported in Finland, Italy, and Denmark [Gatti et al 2024]. The global burden of celiac disease is high, including 50% of individuals that remain undiagnosed [Gatti et al 2024]. There is thought to be a genuine increase in celiac incidence, beyond increased awareness and diagnostic testing, likely due to environmental factors [Caio et al 2019, King et al 2020]. Many environmental influences on celiac incidence have been reported, including use of antibiotics in the first year of life, timing of gluten introduction to infants, mode of delivery, and others [Caio et al 2019, King et al 2020].

The prevalence of celiac disease is increased in individuals with the following disorders [NIH Consensus Committee 2005]:

• Down syndrome (prevalence of celiac disease: 5%-12%)
• Turner syndrome (~3%)
• Williams syndrome (3%-10%)
• Selective IgA deficiency (~2%-10%)
• Type 1 diabetes mellitus (~6%)
• Sjögren syndrome (~5%)
• Autoimmune thyroid disease (~2%-4%)

Other (Non-Celiac) Gluten-Related Disorders

Allergic (wheat allergy). An adverse immunologic (allergic) reaction to proteins in wheat is characterized by production of anti-wheat immunoglobulin (Ig) E antibodies. Varieties of wheat allergy include: 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 Cianferoni [2016]. 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 United States. Wheat allergy is not commonly considered in the differential diagnosis of celiac disease, though individuals with a wheat allergy do require a gluten-free diet.

Non-celiac gluten or wheat sensitivity. Non-celiac gluten or wheat sensitivity is considered to occur in individuals with symptoms that respond to withdrawal of gluten and for whom celiac disease and wheat allergy have been ruled out. 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., tissue transglutaminase or endomysial antibody IgA) [Lebwohl et al 2015]. Although some may have elevated anti-native gliadin IgG antibodies, 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 or wheat sensitivity can present with intestinal symptoms (including irritable bowel syndrome) and extraintestinal symptoms similar to those of celiac disease [Catassi et al 2023]. A review and meta-analysis of studies with nearly 50,000 participants from 16 countries determined that the overall prevalence of self-reported non-celiac gluten/wheat sensitivity (NCGWS) was 10% (varying from 0.7% in Chile to 36% in Saudi Arabia, with 5% in the US and 36% in the UK) and was approximately two times higher in females than in males [Shiha et al 2025]. The most common symptoms reported were bloating, abdominal pain, and fatigue, while individuals were more likely to report anxiety, depression, and irritable bowel syndrome than controls. Among individuals reporting NCGWS, 40% were adhering to a gluten-free diet [Shiha et al 2025].

Self-reported non-celiac gluten sensitivity is an umbrella term, not a single condition, and etiologies are unclear but may include a gut-brain interaction or reaction to fermented oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) [Shiha et al 2025]. A survey in the UK revealed that self-reported non-celiac gluten sensitivity has been increasing, likely due to many factors including an impression that the gluten-free diet is healthy for everyone, which is not the case [Croall et al 2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with celiac disease, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The care of a newly diagnosed individual should be provided by a team including a gastroenterologist, primary care physician, and experienced nutritionist; see Figure 3 and Rubio-Tapia et al [2023].

Figure 3.

Suggested schedule of assessments at celiac disease diagnosis and at follow-up. Reproduced with permission from Rubio-Tapia et al [2023]

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in this section are recommended.

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.
• Physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations should be performed annually or as needed.
• Measure hepatic profile (including aspartate aminotransferase, alanine aminotransferase, bilirubin, and alkaline phosphatase) and thyroid-stimulating hormone annually.
• Stool gluten testing can be used on an individual basis to assess for unidentified dietary sources of gluten in the stool from one to four days after suspected consumption.
• Follow-up biopsy can be considered to confirm healing of intestinal villi. Because some individuals on a strict gluten-free diet can heal gradually, this should typically be done at least two years after the initial diagnosis.

The most frequently used classification of intestinal damage is the Marsh-Oberhuber classification [Oberhuber et al 1999] (see Table 5).

Agents/Circumstances to Avoid

Avoid dietary gluten.

Evaluation of Relatives at Risk

Celiac human leukocyte antigen (HLA) genetic testing of first-degree relatives of a proband (including young children) for celiac-associated HLA-DQA1 and HLA-DQB1 allele(s) and determination of HLA-DQ status can be used to 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. This may be extended to second-degree relatives among families with multiple affected relatives [Rubio-Tapia et al 2023].

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

• Individuals who do not have celiac-associated HLA-DQA1 or HLA-DQB1 allele(s) do not need to undergo serologic screening for celiac disease (the presence of specific celiac-associated HLA-DQA1 and HLA-DQB1 allele[s] that encode the alpha and beta chains of the HLA-DQ heterodimers involved in the immune response to gluten is required for the development of celiac disease).
• Individuals at risk for celiac disease based on HLA-DQ status (determined by HLA-DQA1 and HLA-DQB1 genetic testing) (see Table 2) are followed by celiac serologic testing. Asymptomatic individuals with negative celiac serologic test results while on a gluten-containing diet should undergo serum tissue transglutaminase (tTG) immunoglobulin (Ig) A testing at regular intervals to screen for the development of celiac-associated antibodies [Husby et al 2012, Faye et al 2019]. The screening frequency may be individualized depending on HLA genetic risk for celiac disease and family history [Meijer et al 2022].
• Small bowel biopsy is recommended when celiac serologic testing is positive.

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

Therapies Under Investigation

Several novel therapeutic approaches that potentially could be used as alternatives for or additives to a gluten-free diet are being investigated (reviewed in Discepolo et al [2024]).

• An inhibitor to tTG is currently in clinical trials (EU Clinical Trials register 10007864).
• Detoxifying gluten using oral proteases is being investigated. Latiglutenase and TAK-062, two glutenases, are currently in clinical trials (NCT03585478, NCT05353985).
• Peptides that block the binding groove of DQ2 and DQ8 to prevent activation of gluten-sensitive T cells are in clinical trials (NCT05425446).
• Cytokine blockers, particularly for refractory celiac disease, are being investigated. Of particular interest are blockers of anti-IL15 antibody (NCT04424927).
• Gluten tolerance-inducing therapies are currently in clinical trials (NCT04530123, NCT05574010).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Risk to Family Members

Celiac disease is a complex multifactorial disorder. The risk to family members of a proband with celiac disease depends on their human leukocyte antigen (HLA) genetic risk (i.e., their HLA-DQ status; see Table 2), less well-recognized variants in non-HLA genes, exposure to dietary gluten, and the involvement of additional environmental influences. Risk is also influenced by sex (females are at greater risk) and country of residence, with Sweden having the greatest risk based on data from a pediatric study [Stahl et al 2023].

First-degree relatives of individuals with celiac disease are at a much higher risk for developing the disease compared to the general population [Jansson-Knodell et al 2025].

• The prevalence of celiac disease among screened first-degree relatives has been reported to be as high 44.4% [Nellikkal et al 2019].
• In a study including 250 sibs and 584 parents of individuals with celiac disease, 17.6% of sisters and 10.8% of brothers were affected (overall incidence in sibs of 13.6%), while incidence in parents was 3.4% [Megiorni et al 2009].
• In a large meta-analysis, the global prevalence of celiac disease in pooled first-degree relatives of individuals with celiac disease was 7% for celiac disease with characteristic histopathology on duodenal biopsy and 11% for positive celiac serologic results (elevated serum tissue transglutaminase [tTg] immunoglobulin [Ig] A) [Karimzadhagh et al 2024]. Prevalence was higher in daughters (23%) and sisters (14%) than in brothers (9%) and sons (6%), and lowest in parents (5%). In this meta-analysis, seroprevalence of celiac disease in first-degree relatives was highest in Asia (14%), followed by North America (11%), Europe (9%), and South America (9%). Of individuals with a diagnosis of celiac disease based on duodenal biopsy, 34% were asymptomatic, supporting a proactive approach to screening in asymptomatic as well as symptomatic first-degree relatives to aid in early detection and management of celiac disease [Jansson-Knodell et al 2025, Karimzadhagh et al 2024].

HLA-DQ status is the strongest determinant of celiac disease susceptibility.

• In infant feeding studies with longitudinal follow-up of children with an affected first-degree relative, children with "high-risk HLA" (homozygous for a DQB1*02 allele with HLA-DQ status DQ2.5 + DQ2.5 or DQ2.5 + DQ2.2) had a much higher risk of celiac disease at age ten years than children with "standard-risk HLA" (other celiac-associated HLA-DQA1 and HLA-DQB1 allele[s]) (26% vs 16% for overt celiac disease and 38% vs 19% for celiac disease seropositivity) [Lionetti et al 2014].
• In a gluten feeding intervention study of infants at high risk for celiac disease (based on the presence of DQ2 or DQ8 and a family history of least one first-degree relative with celiac disease), the cumulative celiac disease incidence in the highest-risk group (DQ2.5 + DQ2.5 or DQ2.5 + DQ2.2) at age three, four, and five years was 14.9%, 23.9%, and 26.9%, respectively. In this group, celiac disease developed earlier and at a significantly higher frequency than in other celiac HLA genetic risk groups. For example, the incidence of celiac disease in the group with the lowest HLA genetic risk in the study (DQ2.2 + other HLA-DQ haplotype) was 1.6% at age three years, where "other" refers to any HLA-DQ haplotype other than DR3-DQ2, DR7-DQ2, DR4-DQ8, or DR5-DQ7 [Vriezinga et al 2014].

Inheritance of celiac disease HLA susceptibility is complex, as the HLA-DQA1 and HLA-DQB1 celiac-associated alleles encoding DQ2 can be inherited together from one parent (on the same chromosome) or from both parents (on separate chromosomes).

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.

Prenatal Testing and Preimplantation Genetic Testing

While technically possible, prenatal testing of celiac-associated HLA variants is not relevant in this complex disorder because celiac-associated HLA-DQA1 and HLA-DQB1 alleles are common in the general population and are predisposing to but not predictive of celiac disease.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Celiac disease is a complex 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. There is interplay between several immune pathways and involvement of additional environmental influences other than the key trigger, dietary gluten. The etiologies of many of the extraintestinal manifestations have not been fully elucidated [Verdu & Schuppan 2021].

The Immunologic Mechanisms of Celiac Disease

Inflammatory mechanisms and immunologic responses in the digestive system provide protection from bacteria, toxins, and other foreign elements in the food and water supply. Immunoglobulin (Ig) A, made in abundance by the intestinal immune system, is important in local (mucosal) immunity. In celiac disease, an inappropriate immune response leads to chronic inflammation and damage of the small intestinal mucosa. The two main categories of immune response involved in celiac disease are the adaptive immune response (human leukocyte antigen [HLA] specific) and the innate immune response (independent of HLA type), and both are needed for the development of celiac disease with tissue damage [Voisine & Abadie 2021, Patt et al 2023]. Key drivers of celiac pathophysiology are the main environmental trigger (gluten peptides as antigen, deamidated by tissue transglutaminase [tTG]), the key genetic predisposing factor (HLA DQ2 and DQ8 molecules to which the peptides bind), ensuing anti-gluten inflammatory CD4⁺ T-cell response, B-cell response creating anti-gliadin and autoantibodies (tTG IgA), and killing of intestinal epithelial cells by cytotoxic CD8⁺ T cells [Voisine & Abadie 2021].

Genetic susceptibility to celiac disease. Genetic susceptibility to celiac disease is conferred by the presence of specific HLA-DQA1 and HLA-DQB1 alleles and haplotypes that encode the major histocompatibility complex (MHC) class II heterodimers DQ2 and DQ8, glycoproteins found on the surface of antigen-presenting cells (APCs), particularly dendritic cells, B cells, and plasma cells. This is estimated to account for approximately 50% of celiac disease heritability. Celiac-associated non-HLA genes identified to date account for ~14% of heritability, so not all genetic factors have been determined.

The great majority (>90%) of individuals with celiac disease have DQ2.5, and most of the remainder have DQ8 (see Table 1 and Table 2). A small percentage of individuals who do not have DQ2.5 or DQ8 have DQ2.2 (with the beta chain encoded by DQB1*02, the beta half of DQ2) or DQ7.5 (with the alpha chain encoded by DQA1*05, the alpha half of DQ2).

DQ2 and DQ8 confer susceptibility to celiac disease by presenting the deamidated gliadin subcomponent of gluten to specific CD4⁺ T helper cells of the immune system in the intestinal mucosa (see Figures 4, 5, and 6) [Sollid & Lundin 2014, Voisine & Abadie 2021, Abadie et al 2024].

Figure 4.

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

Figure 5.

The landscape of celiac disease pathogenesis including interplay between several immune pathways in distinct gut locations Digestion-resistant gluten peptides from dietary gluten in the lumen are transported across the epithelium into lamina propria, (more...)

Figure 6.

Celiac disease is a multifactorial complex autoimmune disorder that requires the interplay between genetics, innate and adaptive immunity, and environmental triggers to cause tissue destruction. In individuals with HLA-DQ2, HLA-DQ8, and/or other celiac-associated (more...)

Immunopathogenic mechanisms. For an overview of celiac pathophysiology, see Voisine & Abadie [2021], Levescot et al [2022], and Doyle et al [2025]. See Figure 5 for depiction of the steps of celiac disease development and the interplay between several immune pathways.

Gliadin (a component of gluten) contains a proline-rich section that is resistant to digestion by proteolytic enzymes in the intestinal lumen and results in a 33-mer peptide that can be transported across the epithelial barrier from the intestinal lumen to the lamina propria by a well-characterized process [Verdu & Schuppan 2021]. Usually there is oral tolerance to dietary antigens, but in individuals genetically predisposed to celiac disease, oral tolerance is lost and leads to a gluten-specific pro-inflammatory T-cell response [Voisine & Abadie 2021].

Adaptive immune response (HLA dependent). Details of the adaptive immune response (HLA dependent) are described in the legends of Figures 5 and 6. The adaptive pro-inflammatory CD4⁺ T-cell response is a driver toward tissue damage / villous atrophy, but damage does not occur without concomitant activation of intraepithelial cytotoxic lymphocytes (IE-CTLs) through an innate immune pathway involving gluten directly.

Innate immune response to gluten and epithelial stress. In addition to the adaptive immune response, an innate response to gluten involving intraepithelial CD8⁺ cytotoxic T lymphocytes (IELs) is also key to the pathogenesis of celiac disease. The gluten-specific HLA-restricted T-cell response is central but not sufficient to cause mucosal damage [FitzPatrick et al 2025]. In individuals with celiac disease, gluten independently induces epithelial stress through overproduction of interleukin-15 cytokine (IL-15) from CD8⁺ IE-CTLs, which acquire cytotoxic NK (natural killer)-like properties. More details are provided in the legends of Figures 5 and 6. Individuals with potential celiac disease who have anti-tTG antibodies (and hence an adaptive immune response to gluten) lack villous atrophy and do not show accumulation of IE-CTLs with the NK phenotype or upregulation of IL-15 [Voisine & Abadie 2021]. A new twist from recent studies is that intestinal epithelial cells are not only a target of immune-mediated damage but can express celiac-associated MHC class II heterodimers and contribute to the anti-gluten T-cell response [Rahmani et al 2024].

Additional environmental factors. Numerous additional environmental factors (both external and internal) have been reported to be involved in the development of celiac disease. Although details are beyond the scope of this GeneReview, a few examples are amylase trypsin inhibitor (ATI) proteins in wheat that stimulate innate responses, certain microbes, changes in intestinal permeability of the epithelial barrier, and the microbiota [Verdu & Schuppan 2021, Matera & Guandalini 2024].

Regarding the microbiota, a literature review of 364 papers led to the conclusion that individuals with celiac disease have an altered composition of the gut microbiota compared to healthy individuals (though the changes could be the cause and/or the consequence of celiac disease); the microbiota influences the inflammatory response to gluten, the loss of gluten tolerance, and the pathogenesis progression, and the gluten-free diet fails to rectify the dysbiosis [Matera & Guandalini 2024]. Studies have shown that the microbiota composition of infants with genetic susceptibility to celiac disease is different from that of infants not at genetic risk for the disorder [Matera & Guandalini 2024]. More prospective longitudinal studies are needed to gain a better understanding of the role of the microbiota in celiac disease development [Matera & Guandalini 2024].

Acknowledgments

We would like to acknowledge Ruth Petzold Koester, PhD, F(ACHI), previous HLA Laboratory Director, DNA Identification Division, Labcorp, and Megan Shaffer, PhD, S(ACHI), Technical Director, DNA Identification Division, Labcorp, for important discussions.

We would also like to thank Dr Ludvig Sollid, Professor, Centre for Immune Regulation, Department of Immunology, Oslo University Hospital for sharing his knowledge and insight.

The authors note the following centers specializing in care of individuals with celiac disease:

• Columbia University
  celiacdiseasecenter.columbia.edu
• University of Chicago
  www.uchicagomedicine.org
• Children's Hospital Colorado
  www.childrenscolorado.org
• Mayo Clinic
  www.mayoclinic.org
• Vanderbilt University
  www.vanderbilthealth.com

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

• 4 December 2025 (sw) Comprehensive update posted live
• 31 January 2018 (sw) Comprehensive update posted live
• 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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