Celiac Disease: Laboratory Support for Diagnosis

Celiac disease affects about 1 of every 140 Americans.1 The condition is caused by an immune response to gluten, a protein that is present in many grains and food products.2 Consuming gluten inflames the small intestine, leading to abdominal pain, bloating, and constipation or diarrhea.2 In addition, adults with celiac disease may experience weight loss, and infants may exhibit failure to thrive.2 In most patients, removing gluten from the diet will resolve symptoms.

Laboratory testing is important to help diagnose celiac disease.1,2 Prompt diagnosis may help prevent certain potentially serious complications.2-4 This article will discuss celiac disease and the role of laboratory testing in diagnosis.
Celiac Disease

What is Celiac Disease?
Celiac disease is an autoimmune condition triggered by gluten, which is a mixture of alcohol-soluble plant storage proteins found in grains including wheat, rye, barley, spelt, and kamut.2 The immune response damages intestinal villi, resulting in malabsorption and related complications such as bone mineral loss.2,4 More serious consequences from untreated celiac disease include small-bowel adenocarcinoma and lymphoma, as well as various neurological complications.2,3 Intestinal villi will recover in most cases if gluten is removed from the diet, but damage due to complications can be permanent.2,3 In rare cases, symptoms and atrophy of the intestinal villi remain after 12 months of a strict gluten-free diet (refractory celiac disease).2,4
Scope and Epidemiology
The overall prevalence of celiac disease in the general population is about 0.7%.1 However, many cases of celiac disease are undetected because of poor disease awareness and lack of serological screening.2 In the United States, the prevalence of celiac disease increased 5-fold between 1975 and 2000; however, the reasons for the increase are not known.2

Celiac disease is slightly more common in women than men, with a 1.5:1 ratio of females-to-males.2 Although the condition can present at any age, 2 peaks of onset have been noted: 1) after weaning and the introduction of gluten in the first 2 years of life, and 2) in the second or third decade of life.2

Celiac disease is more common in persons with insulin-dependent diabetes mellitus; autoimmune thyroiditis; Down, Turner, or Williams syndromes; or a family history of celiac disease in a first-degree relative.2,4,5 Celiac disease is also more common in persons with selective IgA deficiency, an immune system disorder in which IgA levels are low or absent.6 The condition can be associated with recurrent pneumonia, ear infections, sinus infections, allergies, asthma, and diarrhea.
Genetic Predisposition
Patients with celiac disease have a genetic predisposition: about 90% to 95% of celiac disease patients carry the HLA-DQ2 allele, and about 5% carry the HLA-DQ8 allele.4 These alleles are also common in the general population, so detection does not equal diagnosis. However, the absence of these markers can be helpful in excluding celiac disease.
Diagnosis of Celiac Disease
Celiac disease may be diagnosed based on signs and symptoms. However, other conditions such as food allergies, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) may have a similar presentation. The presence of specific autoimmune antibodies is consistent with a diagnosis of celiac disease.2,4 Endoscopy and histopathological examination of small intestine biopsy specimens is the gold standard for diagnosis.2,4 Resolution of symptoms after gluten is removed from the diet confirms a diagnosis of celiac disease in most cases. While genetic testing is not useful for diagnosing celiac disease, it is useful for ruling out the condition.2,4
Autoantibody Testing
Levels of celiac disease-specific antibodies decrease after initiating a gluten-free diet, so the American College of Gastroenterology (ACG) recommends that patients undergoing serologic testing for celiac disease should be on a gluten-containing diet.4 Antibody tests in the evaluation of suspected celiac disease include
  • Tissue transglutaminase antibodies (tTG IgA and tTG IgG): tTG IgA is recommended as a first-line marker,4 with a sensitivity of 95% to 98% and a specificity of 94% to 95% for diagnosing celiac disease.5 tTG IgG has a lower sensitivity (40%) for celiac disease but is highly specific (95%).5
  • Endomysial IgA antibody (EMA IgA): EMA IgA has a lower sensitivity (>90%) but higher specificity (>95%) than tTG IgA for celiac disease. It can be used to confirm positive tTG IgA test results.5
  • Deamidated gliadin peptide IgG antibody (DGP IgG) has a sensitivity of 80% and a specificity of 98% for celiac disease.5

Though uncommon, seronegative celiac disease has been reported. In seronegative disease, autoantibody test results are negative, but atrophy of the intestinal villi and signs of severe malabsorption are present.2,4
Genetic Testing
The ACG recommends HLA typing to rule out a diagnosis of celiac disease in certain situations, such as4
  • Inconsistent serology and histology test results (eg, positive serology and normal histology)
  • Equivocal small-bowel histological findings in seronegative patients
  • Patients with Down syndrome7,8
  • Patients on a gluten-free diet if they are being considered for gluten challenge and 1) have not been tested for celiac before starting a gluten-free diet; or 2) have suspected refractory celiac (persistent symptoms after 6-12 months on a gluten-free diet) and a questionable original diagnosis of celiac disease7
American College of Gastroenterology Guidelines: When to Test for Celiac Disease

Testing for celiac disease should be performed in persons with4
  • Symptoms, signs, or laboratory evidence suggestive of malabsorption, such as chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain and bloating
  • Symptoms, signs, or laboratory evidence for which celiac disease is a treatable cause
  • A first-degree family member who has a confirmed diagnosis of celiac disease if they show possible signs or symptoms or laboratory evidence of celiac disease
  • Type 1 diabetes mellitus if there are any digestive symptoms, or signs, or laboratory evidence suggestive of celiac disease
Testing should be considered for4
  • Asymptomatic relatives with a first-degree family member who has a confirmed diagnosis of celiac disease
  • Individuals with unexplained elevations of serum aminotransferase levels

How the Laboratory Can Help

Quest Diagnostics offers tests for the different antibodies that are associated with celiac disease and comprehensive testing panels that may help to more quickly establish a diagnosis of celiac disease.

The Celiac Disease Comprehensive Panel with Gliadin Antibody (IgG) (test code 36336) begins by testing specimens for tTG IgA (test code 8821). Specimens positive for tTG IgA are tested for EMA IgA (test code 15064), which may increase specificity for celiac disease. This panel also tests all specimens for total IgA (test code 539). A total IgA level below the reference range is suggestive of IgA deficiency and reflexes to IgG-based tests (tTG IgG [test code 11070] and DGP IgG [test code 11212]); these tests are generally less sensitive than tTG IgA testing for celiac disease but are useful in the context of IgA deficiency.

The Celiac Disease Comprehensive Panel with Gliadin Antibodies (Age 5 and under) (test code 36331) is used to assist in the diagnosis of celiac disease in children ≤5 years old. All specimens are initially tested for DGP IgA and DGP IgG (test code 8889), in addition to tTG IgA (test code 8821), which has reduced sensitivity in young children. Specimens positive for tTG IgA are tested for EMA IgA (test code 15064). This panel also evaluates all specimens for total IgA (test code 539); a total IgA level below the reference range is suggestive of IgA deficiency and reflexes to tTG IgG (test code 11070).

The HLA Typing for Celiac Disease (test code 17135) assay tests for HLA alleles associated with celiac disease (HLA-DQ2 and HLA-DQ8). A negative result is useful for ruling out celiac disease in some situations, such as patients with discrepant celiac-specific serology and small intestine biopsy findings.4

Quest also offers panels to help diagnose conditions with similar symptoms to celiac disease such as the Inflammatory Bowel Disease Differentiation Panel (test code: 16503) which can help distinguish Crohn’s disease from ulcerative colitis. The panel includes: ANCA Screen with Reflex to ANCA Titer (test code 70171); Myeloperoxidase Antibody (MPO) (test code 8796);     Proteinase-3 Antibody (test code 34151); Saccharomyces cerevisiae Antibodies (ASCA) (IgG) (test code 10294); Saccharomyces cerevisiae Antibodies (ASCA) (IgA) (test code 10295).

The Calprotectin, Stool (test code: 16796) assay can also help differentiate IBD (Crohn’s disease, ulcerative colitis) from celiac disease and IBS.

Quest also offers food allergy testing, with reflex to component testing. Specific IgE testing for allergen components can help identify the specific protein in a food that is causing the allergic reaction. Knowing the specific protein causing the reaction can help determine a person’s risk of a severe systemic reaction vs a mild, localized reaction.

Panel components can be ordered separately. Reflex tests are performed at an additional charge and are associated with an additional CPT code.

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  1. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107:1538-1544.
  2. Caio G, Volta U, Sapone A, et al. Celiac disease: a comprehensive current review. BMC Med. 2019;17:142. doi:10.1186/s12916-019-1380-z
  3. Campagna G, Pesce M, Tatangelo R, et al. The progression of coeliac disease: its neurological and psychiatric implications. Nutr Res Rev. 2017;30:25-35.
  4. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656-676.
  5. Pelkowski TD, Viera AJ. Celiac disease: diagnosis and management. Am Fam Physician. 2014;89:99-105.
  6. Yazdani R, Azizi G, Abolhassani H, et al. Selective IgA deficiency: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Scand J Immunol. 2017;85:3-12.
  7. Hill ID, Fasano A, Guandalini S, et al. NASPGHAN clinical report on the diagnosis and treatment of gluten-related disorders. J Pediatr Gastroenterol Nutr. 2016;63:156-165.
  8. Villalta D, Tonutti E, Prause C, et al. IgG antibodies against deamidated gliadin peptides for diagnosis of celiac disease in patients with IgA deficiency. Clin Chem. 2010;56:464-468. 

Content reviewed 7/2020