Celiac Disease

Chapter: Celiac Disease
McMaster Section Editor(s): John K. Marshall, Paul Moayyedi
Section Editor(s) in Interna Szczeklika: Witold Bartnik†, Małgorzata Szczepanek, Władysław Januszewicz
McMaster Author(s): Maria Ines Pinto-Sanchez, Elena F. Verdu
Author(s) in Interna Szczeklika: Hanna Szajewska
† Deceased.
Additional Information

Definition, Etiology, PathogenesisTop

Celiac disease (CD) is an autoimmune enteropathy triggered by gluten and developing in patients that carry the HLA-DQ2 or HLA-DQ8 haplotype.

Gluten is the collective name for a group of proteins found in wheat (gliadins and glutenins), rye (secalin), and barley (hordein). Gluten proteins have a high concentration of the amino acids proline and glutamine, rendering them resistant to enzymatic degradation by digestive enzymes. As a result, large and potentially immunogenic peptides may reach the mucosa of the small intestine and initiate an immune response. The high proline and glutamine content in gluten peptides also renders them excellent substrates for tissue transglutaminase type 2 (tTG2). tTG2 is a ubiquitous intracellular enzyme that is released extracellularly and activated during inflammation. tTG2 deamidates gluten peptides, which converts glutamine to negatively charged glutamic acid residues, increasing their binding affinity to HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells. Gluten-specific T cells from patients with CD preferentially recognize deamidated gluten peptides and produce the type 1 helper T cell (Th1) cytokines interferon gamma and interleukin 21. Gluten-specific Th1 cells also provide help for the activation of B cells to form antigluten and anti-tTG2–producing plasma cells. The presence of antibodies to tTG2 (anti-tTG2 IgA) or endomysial antibodies (EmAs) and/or IgA or IgG antibodies against deamidated forms of gliadin peptides (DGPs) is a valuable tool for diagnosing CD. In clinical practice IgA antibodies to tTG2 along with total IgA levels to exclude IgA deficiency are the primary serologic diagnostic tests used. Duodenal biopsies to assess the presence of enteropathy are encouraged to confirm diagnosis.

Contrary to what was previously thought, the onset of CD occurs at any age, and today the disease is more often diagnosed in adulthood. Although ~30% of the world population carries the HLA-DQ2 or HLA-DQ8 genes, only 1% will develop the disease. This together with the rising prevalence of CD in the past 40 years suggests that unknown environmental factors may also play a role in disease pathogenesis.

Clinical Features and Natural HistoryTop

1. Signs and symptomsCD is frequently asymptomatic and diagnosis often follows a screening test. However, it may present with different gastrointestinal and extraintestinal manifestations, with extraintestinal symptoms usually predominating in adults:

1) Gastrointestinal: Chronic diarrhea, abdominal pain, bloating, constipation, recurrent aphthous stomatitis, vomiting, reflux, micronutrient deficiencies, steatohepatitis, and weight loss (rare).

2) Extraintestinal:

a) Cutaneous: Dermatitis herpetiformis (Duhring disease: Figure 6.1-7; ~15%-25% of patients), urticaria, atopic dermatitis, psoriasis (~4%).

b) Hematologic: Iron deficiency anemia (~50% of patients at diagnosis), thrombocytosis, IgA deficiency, leukopenia, neutropenia.

c) Gynecologic: Delayed puberty (including delayed menarche), infertility, recurrent abortions.

d) Neurologic: Central nervous system: seizures, migraine, ataxia; peripheral neuropathy.

e) Psychological: Anxiety, depression.

f) Bones: Osteopenia, osteoporosis, bone fractures.

g) Other: Muscle weakness, tetany, short stature, dental enamel defects.

2. Clinical classification of CD: Table 6.1-5.

3. Natural history: Undiagnosed or untreated CD may lead to complications, some of them serious (eg, increased risk of certain types of cancers). The clinical course of CD depends on compliance with a gluten-free diet (GFD). Poor compliance is associated with increased risk of complications and mortality. The most common complications associated with CD:

1) Gastrointestinal: Pharyngeal or esophageal cancer, lymphoma or cancer of the small intestine, refractory CD (symptoms persisting despite compliance with a GFD).

2) Hematopoietic: Non-Hodgkin lymphoma.

3) Urogenital: Infertility, recurrent miscarriage, premature birth, premature menopause.

4) Musculoskeletal: Osteoporosis and increased risk of bone fractures.

DiagnosisTop

CD may be suspected in:

1) Symptomatic patients with:

a) Gastrointestinal symptoms and signs: Diarrhea, weight loss, gas/bloating, constipation (more commonly in children), elevated aminotransferase levels.

b) Extraintestinal symptoms and signs: Iron deficiency anemia, dermatitis herpetiformis, osteoporosis, neuropsychiatric conditions (eg, neuropathy, ataxia).

2) Patients with associated conditions: Autoimmune thyroiditis, type 1 diabetes mellitus, Down syndrome, other autoimmune conditions.

3) First-degree family members of patients with CD.

Diagnostic tests should be performed in patients consuming a gluten containing diet (≥6 weeks of daily intake of ≥1 meal containing gluten).

Diagnostic Tests

1. General laboratory tests:

1) Hemoglobin to investigate for anemia (a frequent abnormality in adults); most likely iron deficiency anemia, rarely megaloblastic anemia.

2) Micronutrients: Reduced serum levels of iron, folic acid, calcium, vitamins D, B6, B12, zinc, copper, selenium.

3) Hypoalbuminemia (due to protein loss into the gastrointestinal tract).

4) Liver enzymes (transient elevation of liver aminotransferases is seen in active CD).

2. Specific serology: IgA antibodies to tissue transglutaminase (tTG) (total IgA levels must also be measured to exclude IgA deficiency), EmA IgA, and DGPs are used for the diagnosis of CD. tTG IgA antibody is the preferred single test for detection of CD in individuals aged >2 years.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013 May;108(5):656-76; quiz 677. doi: 10.1038/ajg.2013.79. Epub 2013 Apr 23. PubMed PMID: 23609613; PubMed Central PMCID: PMC3706994. Because of their low sensitivity and specificity, the use of antigliadin antibodies (IgA and IgG) for the diagnosis of CD is discouraged. In patients with IgA deficiency IgG antibodies to tTG2 or DGPs need to be measured. Alternatively, DGP IgG can be added to tTG IgA to increase sensitivity.

Sensitivity and specificity differ depending on the type of antibodies and substrate. The most sensitive and specific test is tTG IgA, which is considered the first-line choice for the diagnosis of CD. The new DGP IgA or IgG have lower sensitivity compared with tTG IgA but may detect CD in some patients who are falsely negative for tTG. DGP IgG is also useful as a first-line test in addition to tTG IgA, especially in those with IgA deficiency. EmA IgA is the most specific test for the diagnosis of CD, but it requires immunofluorescence and is operator-dependent. EmA IgG has lower sensitivity compared with EmA IgA.

Indications for serologic studies:

1) Case finding in patients with suspected CD.

2) Screening in high-risk groups (eg, family members of patients with diagnosed CD; patients with related autoimmune diseases, such as type 1 diabetes mellitus or hypothyroidism).

3) Monitoring of compliance with a GFD. In compliant patients results of serologic tests normalize in the first year after diagnosis.

3. Endoscopy: Grooved or scalloped margins of duodenal folds, reduction in the number of folds (which are flattened or atrophic), a mosaic pattern of the mucosal surface, and prominent submucosal blood vessels (normally not visible).

4. Histologic examination of samples of the small intestinal mucosa is key for the diagnosis of CD, particularly in adult patients. The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) criteria propose specific clinical situations where biopsy could be avoided in the diagnosis of CD in children. Tissue samples (≥4 biopsy specimens collected from the second and third portion of the duodenum and 1-2 specimens from the duodenal bulb) are usually obtained by esophagogastroduodenoscopy (EGD). A typical histologic finding is villous atrophy accompanied by high intraepithelial lymphocyte counts and hyperplasia of intestinal crypts (villous atrophy). The Marsh classification includes types 0 to 2 with increasing intraepithelial lymphocyte counts and increasing degree of hyperplasia and type 3 with villous atrophy (3a, mild; 3b, moderate; 3c, severe).

5. Genetic testing: The great majority (95%-99%) of patients with CD carry the HLA-DQ2 haplotype and the remaining patients (5%-10%) carry HLA-DQ8. In rare cases (<1%) patients not carrying these heterodimers express the other half of the DQ2.5 heterodimer (DQ7.5). Therefore, the absence of HLA-DQ2 or HLA-DQ8 molecules practically excludes the diagnosis of CD. However, ~30% of the general population carries HLA-DQ2 and HLA-DQ8 in the absence of CD; therefore, HLA-DQ2 and HLA-DQ8 should not be used for the diagnosis of CD.Evidence 2Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Al-Toma A, Volta U, Auricchio R, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019 Jun;7(5):583-613. doi: 10.1177/2050640619844125. Epub 2019 Apr 13. Review. PubMed PMID: 31210940; PubMed Central PMCID: PMC6545713. HLA-DQ2/DQ8 testing is indicated to exclude CD in the following situations:

1) Marsh type 1 or 2 histology in patients with negative CD serology.

2) Assessment of the risk for CD in patients on a GFD not previously investigated for CD.

3) Discrepancy between CD-specific serology and histology results.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Al-Toma A, Volta U, Auricchio R, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019 Jun;7(5):583-613. doi: 10.1177/2050640619844125. Epub 2019 Apr 13. Review. PubMed PMID: 31210940; PubMed Central PMCID: PMC6545713.

Diagnostic Criteria

Positive serologic study results and typical histologic findings. General diagnostic algorithm: Figure 6.1-8.

Differential Diagnosis

Differential diagnosis should include other causes of enteropathy (villous atrophy): chronic giardiasis, tropical sprue, protein malnutrition, anorexia nervosa, food hypersensitivity (lesions are usually focal), viral infection (including HIV), bacterial infection (eg, tuberculosis), bacterial overgrowth syndrome, Whipple disease, postirradiation complications, immunodeficiency (eg, hypogammaglobulinemia, common variable immunodeficiency), Crohn disease, ulcerative colitis, and lymphoma of the small intestine.

TreatmentTop

The only currently available treatment for CD is adherence to a strict GFD. Very small amounts of gluten (50 mg or a breadcrumb) can induce changes ranging from villous to crypt abnormalities in patients with CD.

1. GFD: Lifelong elimination of all wheat, rye, and barley products.

Products allowed: Dairy products (liquid and powdered milk, hard cheese, cottage cheese, cream, eggs); all meats and meat products (note: diced bread and semolina may be added to certain meat products such as sausages, pates, liverwurst), offal (liver, lungs, kidneys), fish; all fruits and vegetables; nuts; rice, corn, soybeans, tapioca, buckwheat; all fats; sugar, honey; spices, salt, and pepper; coffee, tea, cocoa; gluten-free breads, cakes, and desserts. All gluten-free products are labeled with a crossed-grain symbol.

Products not allowed: Wheat, rye, barley, and noncertified gluten-free oat products (as they are often contaminated with gluten); bread rolls, white bread, whole-grain bread, crispbread; pasta; semolina, barley; other products containing gluten, such as cakes, biscuits, confectionery.

Supplementation of iron, folic acid, calcium, and sometimes vitamin B12 may be indicated (in case of deficiency). Repeated monitoring of the effectiveness of treatment includes evaluation of diet and nutritional status of the patient. Undetectable levels of tTG, DGP, or EMA are an indirect confirmation of compliance with a GFD.

2. Immunosuppressive drugs (eg, glucocorticoids, azathioprine, cyclosporine [INN ciclosporin]) may be used in refractory CD not responding to dietary restrictions.

3. Treatment difficulties and future pharmacologic therapies: A strict GFD is difficult to achieve and follow in the long term. Without proper monitoring, following a GFD can lead to nutritional deficiencies. The diet is also expensive. Therefore, noncompliance, either voluntary or through inadvertent contamination, is common. This highlights the need for development of adjuvant therapies to the GFD. Several approaches are being pursued, but so far none is clinically applicable. These potential therapies are to be used as adjuvants of GFD, with the idea to help the patient tolerate minimal amounts of gluten (eg, cross-contamination).

4. Nonresponsive CD: Patients with symptoms and sings of malabsorption (abdominal pain, diarrhea, weight loss) and histologic or serologic abnormalities that persist or recur despite their best efforts to follow a GFD for ≥6 months are considered nonresponsive. The most common reason for nonresponsive CD is inadvertent gluten exposure. Therefore, the first approach is an exhaustive assessment of GFD compliance. Once gluten exposure has been excluded, symptoms may be attributed to other common associated conditions, including exocrine pancreatic insufficiency, small intestinal bacterial overgrowth, inflammatory bowel diseases, microscopic colitis, or functional disorders including irritable bowel syndrome (IBS). Patients with CD may develop an eating disorder leading to persistent symptoms in the follow-up.

A very small proportion of CD patients may develop refractory celiac disease (RCD) (1% of patients with CD or 10% of patients with nonresponsive CD). RCD patients are recognized for persistent symptoms and signs of malabsorption and villous atrophy despite 1 year of following a strict GFD. tTG or CD serology is often negative, supporting the strict compliance with a GFD. There are 2 types of RCD, based on the evidence of aberrant patterns of intraepithelial lymphocytes (IELs). RCD type 1 has a typical pattern of IELs (CD3+ and CD8+) and is associated with better prognosis compared with RCD type 2 (aberrant pattern of IELs: CD3 and CD8), which is associated with mortality and risk of lymphoma of 50% at 5 years. Management of RCD patients is complex and they are usually followed up in specialized centers.

Follow-UpTop

Regular follow-up is recommended after the diagnosis of CD is made.

1. In the first year follow-up visits need to be more frequent to improve dietary adherence, provide psychological support, and optimally motivate the patient to adapt to changes. Even though the evidence on the frequency of visits and type of tests that should be performed is low, guidelines recommend follow-up visits with the physician and ideally a dietitian at 4 to 6 months and 12 months in the first year. The objectives are to symptom assessment, dietary review, CD serologic testing (tTG or DGPs). Nutrients should be monitored at this stage only if they were low at diagnosis. Follow-up endoscopy is not necessary in asymptomatic patients, as mucosal healing is seen only in 30% of individuals in the first year of a strict GFD.

2. After one year or when results of serologic testing become negative, annual visits are recommended to monitor GFD adherence, CD serology (tTG or DGPs), and nutrients (iron, copper, zinc, selenium, folate, vitamin B12). Bone density measurements may be repeated at 1 to 2 years if the results were abnormal at diagnosis. If osteopenia or osteoporosis are present, in addition to a strict GFD it is prudent to ensure adequate calcium and vitamin D intake for all patients. Follow-up endoscopy is reasonable after 1 to 2 years of starting a GFD to assess for mucosal healing, especially in patients with severe initial presentation.

3. It is advisable to screen first-degree family members for CD.

4. Assessment by a skilled dietitian is the gold standard for evaluating GFD adherence, but it is time-consuming (each visit takes 45 minutes to 1 hour). New tools for detecting gluten immunogenic peptides in stool or urine by enzyme-linked immunosorbent assay (ELISA) (currently available in research settings) or as point-of-care testing may be useful to identify inadvertent gluten consumption. The tests are highly sensitive (98%) and specific (100%) for detecting gluten consumption within 4 to 5 days (stool) or 1 to 2 days (urine). Gluten can be detected in food by a similar method, using a point-of-care sensor.

Tables and FiguresTop

Table 6.1-5. Clinical classification of different forms of celiac disease based on the Oslo consensus

Descriptors of CD

Characteristics

Classical CD

Symptoms and signs of malabsorption including diarrhea, steatorrhea, weight loss; in children growth failure is required

Nonclassical CD

CD presenting without symptoms of malabsorption

Symptomatic CD

Clinically evident GI and/or extraintestinal symptoms attributable to gluten intake

Asymptomatic CD

Lack of GI or extraintestinal symptoms at diagnosis

CD autoimmunity

Increased antibodies to tTG2 or EMAs on ≥2 occasions (if biopsy is negative, it is “potential CD”; if positive, it is CD)

Subclinical CD

CD below threshold for clinical detection without symptoms or signs sufficient to trigger CD-testing in routine practice

Potential CD

Positive CD serology with normal small intestinal mucosa

Genetically at risk for CD

Family members of patients with CD who test positive for HLA-DQ2 and/or HLA-DQ8

Refractory CD

Persistent villous atrophy and malabsorptive symptoms and signs despite strict gluten-free diet for >12 months

CD, celiac disease; EMA, endomysial antibody; GI, gastrointestinal; tTG2, tissue transglutaminase type 2.

Figure 6.1-7. Dermatitis herpetiformis (Duhring disease).

Figure 6.1-8. Approach to the diagnosis of celiac disease in the adult population. Adapted with permission from the Society for the Study of Celiac Disease.

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