Celiac Disease

Clinical characteristics.

Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (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, 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 is established in an individual with:

• Positive celiac serologic testing while on a gluten-containing diet (tissue transglutaminase IgA, anti-deamidated gliadin-related peptide IgA and IgG, endomysial antibody IgA),
• Characteristic histologic findings on small-bowel biopsy, and
• Human leukocyte antigen (HLA) haplotype DQ2 or DQ8 identified by molecular genetic testing of HLA-DQA1 and HLA-DQB1.

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. For individuals unresponsive to a gluten-free diet, evaluation for refractory celiac disease, ulcerative enteritis, T-cell lymphoma, and other gastrointestinal cancers.

Surveillance: For symptomatic individuals responsive to a gluten-free diet abnormal serologies should be followed to normalization, periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations.

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.

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)
• Dermatitis herpetiformis
• Chronic fatigue
• Joint pain/inflammation
• Neurologic symptoms (e.g., peripheral neuropathy, ataxia, seizures, migraines, attention-deficit disorder, poor school performance)
• Osteoporosis/osteopenia
• Infertility and/or recurrent fetal loss
• Short stature and/or failure to thrive
• Delayed puberty
• Dental enamel defects
• Autoimmune disorders
• Individuals with disorders associated with celiac disease (e.g., Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, insulin-dependent diabetes mellitus, Sjögren syndrome, thyroiditis)
• Absence of history of self-limited enteritis and/or tropical sprue

Laboratory findings

• Iron deficiency anemia
• Vitamin and/or mineral deficiencies (e.g., calcium, vitamin D, vitamin B₁₂, folic acid)
• In individuals on a gluten-containing diet:
  • Elevated serum tissue transglutaminase (tTG) IgA
  • Elevated serum anti-deamidated gliadin-related peptide (a-DGP) IgA and IgG
  • Elevated serum endomysial antibody (EMA) IgA; highest specificity (~99%) but sensitivity subject to observer variability
  Note on measurement of serum total IgA to evaluate for IgA deficiency: Selective IgA deficiency is more prevalent in individuals with celiac disease (1:50). In individuals with IgA deficiency, measurement of tTG IgG and DGP-IgG should be performed instead of IgA levels.

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 a-DGP IgA and IgG, and EMA IgA) by identification of:

• 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;
  AND
• Human leukocyte antigen (HLA) haplotype DQ2 or DQ8, as determined by molecular genetic testing of HLA-DQA1 and HLA-DQB1, consistent with an increased risk of celiac disease (see Table 1).

Diagnosis without a duodenal biopsy. Pediatric guidelines from Europe present a pathway for the diagnosis of celiac disease in children that does not include a biopsy. Under these guidelines a diagnosis of celiac disease could be considered in a symptomatic child with a tTG IgA value of more than ten times the upper level of normal, the presence of HLA haplotype DQ2 or DQ8, positive celiac serologic testing on two occasions, and evaluation by a pediatric gastroenterologist [Husby et al 2012]. There is ongoing debate regarding this approach to diagnosis [Reilly et al 2018].

Note: (1) HLA-DQA1 and HLA-DQB1 sequence variants that define haplotypes may be detected by sequencing or by a targeted genotyping assay (methodologies vary). Analysis of HLA genes is complicated by the presence of highly homologous gene family members. (2) Determination of HLA-DQA1 and HLA-DQB1 haplotypes is based on the combination of variants in cis across both genes. Interpretation of sequence data is complicated by detection of uncharacterized sequence variants and uninformative variant zygosity. (3) If haplotype-tag variants from only HLA-DQA1 or HLA-DQB1 are detected, the allele is referred to as a half-DQ2 haplotype (called half DQ-positive). (4) The combination of the haplotypes from homologous chromosomes is called a diplotype. An individual's diplotype at HLA-DQA1 and HLA-DQB1 determines the risk for celiac disease (Table 2).

Clinical Description

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

Figure 2.

Presenting signs/symptoms in celiac disease. The presenting signs/symptoms are the main indications that led to a diagnosis of celiac disease. "Bone disease" refers to evaluation for low bone density. "Incidental" refers to discovery of villous atrophy (more...)

Gastrointestinal manifestations include chronic or recurrent diarrhea, malabsorption, abdominal pain and distention, bloating, vomiting, and weight loss. 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 include 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, abnormal liver function tests, neurologic symptoms, and various secondary autoimmune disorders [Lebwohl et al 2018].

Types of Celiac Disease

Recently a consensus paper redefined the types of celiac disease [Ludvigsson et al 2013].

Classic celiac disease refers to the presence of symptoms of malabsorption such as diarrhea, failure to thrive, and weight loss and may occur in adults and children.

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. Approximately 70% of individuals are diagnosed based on extraintestinal manifestations associated with celiac disease. This group includes monosymptomatic and subclinical forms.

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

Dermatitis herpetiformis, an intensely pruritic rash found most commonly 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, abnormal liver function tests (typically elevated transaminases), fatigue, psychiatric syndromes, and various neurologic conditions including peripheral neuropathy, ataxia, seizures, migraines, attention-deficit hyperactivity disorder, 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].

Potential or latent 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; others may remain in this state or celiac serology testing may become negative. Only those with severe symptoms would be advised to start a gluten-free diet [Volta et al 2016] (see Figure 3).

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" represents the (more...)

Removal of gluten from the diet can result in:

• Reversal of (a) growth failure and (b) reduced bone mineralization in children with celiac disease;
• Decreased frequency of (a) spontaneous abortions and (b) 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's lymphoma;
• Reduced risk of mortality in symptomatic individuals.

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.

• Primary refractory sprue describes the condition in which individuals have never responded to a gluten-free diet.
• 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 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].

Genotype-Phenotype Correlations

Among affected individuals, no difference in clinical severity of celiac disease is observed between those who are homozygous for the DQ2 haplotype and those who are homozygous for the DQ8 haplotype.

Penetrance

The penetrance of celiac disease is low. The risk of developing celiac disease is affected by HLA diplotype (see Table 2).

Prevalence

Celiac disease affects approximately 1% of individuals in the US. Celiac disease is considered to be common in Europe, the US, Australia, Mexico, and some South American countries. The highest reported prevalence of celiac disease is 5.6%, found in a refugee population in North Africa.

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%)
• Insulin-dependent diabetes mellitus (~6%)
• Sjögren syndrome (~5%)
• Autoimmune thyroid disease (~2%-4%)

Other (non-Celiac) Causes of Gluten Sensitivity

Allergic (wheat allergy). An adverse immunologic (allergic) reaction to proteins in wheat is characterized by production of anti-wheat IgE 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 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. 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. 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) [Lebwohl et al 2015]. Although some may have elevated anti-native gliadin IgG 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]. The etiology of non-celiac gluten or wheat sensitivity is unclear. One group has described a series of biomarkers that suggest that the condition is associated with altered intestinal permeability [Uhde et al 2019]. In other double-blind placebo-controlled studies, other dietary, non-absorbable sugars (fructans) were shown to be responsible for symptoms in self-identified gluten-sensitive individuals [Skodje et al 2018].

Evaluations Following Initial Diagnosis

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

• Baseline bone-density test in adults to evaluate for osteoporosis/osteopenia. In those with osteoporosis, vitamin D and parathyroid hormone concentrations should be evaluated.
• Screening tests for anemia, abnormal liver function, and nutrient deficiencies (iron, calcium, vitamin D, vitamin B₁₂, folic acid)
• Evaluation for a coexisting autoimmune disease. Because of the frequent association of celiac disease with autoimmune thyroid disease, thyroid function assessment is often performed [Roy et al 2016].
• Failure to regain weight or gastrointestinal bleeding should prompt evaluation for an intestinal malignancy with radiologic and endoscopic studies.

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 and Rubio-Tapia et al [2013].

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.
• Symptoms may improve rapidly while serologic tests may take up to 12 months to normalize on the gluten-free diet.
• For some individuals, 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 to celiac disease in individuals 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 [Lebwohl et al 2018].
• 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.

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 corticosteroids (e.g., systemic steroids or locally active oral budesonide) and immunosuppressants [Green & Jabri 2003, NIH Consensus Committee 2005, Brar et al 2007, Lebwohl et al 2018].

Surveillance

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.
• Periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations
• 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 is the Marsh-Oberhuber classification (Table 3) [Oberhuber et al 1999].

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 [Husby et al 2012].

Agents/Circumstances to Avoid

Avoid dietary gluten.

Evaluation of Relatives at Risk

Molecular genetic testing of first-degree relatives of a proband for the celiac disease-associated HLA-DQB1/HLA-DQA1 haplotypes DQ2 or DQ8 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.

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-DQB1/HLA-DQA1 haplotypes DQ2 or DQ8 do not need to undergo serologic screening for celiac disease.
• Individuals who have celiac disease-associated HLA alleles (Table 2) 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

Several novel therapeutic approaches that potentially could be used as alternatives for or additives to a gluten-free diet are being investigated (reviewed in Castillo et al [2015] and Rashtak & Murray [2012]):

• Larazotide, a tight junction regulatory peptide that is considered to prevent the passage of gliadin peptides into the mucosa. This drug is in clinical trials.
• Peptides that block the binding groove of DQ2 and DQ8 to prevent activation of gluten-sensitive T cells. The viability of this approach is currently uncertain.
• Transglutaminase (tTG) inhibitors
• Cytokine blockers, particularly for refractory celiac disease. Of particular interest is an anti-IL15 antibody.
• Drugs that selectively inhibit leukocyte adhesion and migration of lymphocytes into inflamed tissues
• Detoxifying gluten, using oral proteases. Latiglutenase, a glutenase, is currently in clinical trials.
• Gluten-sequestering polymers. An oral polymeric resin, P(HEMA-co-SS), binds to gluten and is under study.
• Gluten tolerization. A peptide-based vaccine could desensitize or induce tolerance in individuals with celiac disease. A prototype vaccine, Nexvax2, involving a set of gluten peptides recognized by HLA-DQ2, is in clinical trials.
• Rho/Rho kinase inhibition to theoretically reverse gluten-dependent increase in intestinal permeability [Sollid & Khosla 2011]
• Antibodies to proteins involved in autoimmune pathologies, including anti-IFN-γ, anti-CD3, anti-CD20 therapy, and anti-IL-15. [Sollid & Khosla 2011]
• Another approach: interfering with the homing of gluten-specific T cells to the gut mucosa by using CCR9 antagonists. A Phase II clinical trial is listed in Sollid & Khosla [2011].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.