Celiac Disease

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Celiac Disease in Children and Adolescents

Guidelines from the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) discuss serology testing for celiac disease (CD) evaluation and use of HLA-DQ2/HLA-DQ8 typing.

Recommendations for CD Testing in Children and Adolescents (ESPGHAN, 2012)*

ESPGHAN recommends testing for CD in children and adolescents

  • Who have unexplained
    • Gastroenterological symptoms
    • Poor growth
    • Delayed puberty
    • Iron deficiency anemia
    • Abnormal liver testing
  • Who have one of the following risks for CD (even if asymptomatic)

Laboratory Testing Options

Recommended antibody tests

Individual must be on gluten-containing diet when tested and IgA status must be known1

  • Tissue transglutaminase (tTG) IgA is recommended single screening test
  • Adding endomysial antibody (EMA) IgA testing in high probability individuals increases sensitivity
    • In children <2 yrs with high suspicion of CD – consider antideamidated gliadin peptide (DGP) antibody test to increase sensitivity if tTG and/or EMA IgA is negative

HLA genotyping

  • Absence of HLA-DQ2 or HLA-DQ8 virtually excludes CD
  • Uses (ESPGHAN, 2012, recommendations for children and adolescents; may not be applicable in adults)
    • Should not be routinely performed
    • Strong serologic evidence and clinical suspicion AND desire to avoid small bowel biopsy
    • Negative CD specific antibodies with indeterminate proximal small intestinal biopsy

Available recommended ARUP tests

1Husby S et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):136-60

Indications for Testing

Criteria for Diagnosis

  • Positive tTG IgA (ACG, 2013) and/or EMA IgA serologic test (ESPGHAN, 2012)
  • Biopsy consistent with CD in individuals with normal serum IgA levels
  • tTG IgA or DGP and biopsy, with HLA-DQ genotyping only in event of biopsy/serology disagreement (WGO, 2016)
  • CD may be confirmed without the need for biopsy in symptomatic individuals with high levels of CD-specific antibodies (10 x upper limit of normal) who are HLA-DQ2 or HLA-DQ8 positive (ESPGHAN, 2012)
  • Complete resolution of clinical symptoms and/or a seronegative response following a gluten-free diet
    • Gluten rechallenge not necessary except in patients who did not have initial biopsy or had an uncharacteristic biopsy

Laboratory Testing

Celiac Disease Tests and Characteristics
Testa Characteristics Limitations
Celiac Disease Reflexive Cascade 2008114

Preferred reflex screening test for celiac disease (CD) diagnosis

Depending on initial results from IgA screening, one or more of the following tests may be added for clinical interpretation

  • Tissue transglutaminase antibody, IgA
  • Tissue transglutaminase antibody, IgG
  • Endomysial antibody, IgA by IFA
  • Deamidated gliadin peptide (DGP) antibody, IgA
  • Deamidated gliadin peptide (DGP) antibody, IgG
  • Celiac disease dual antigen screen
 
Celiac Disease Dual Antigen Screen with Reflex 2002026 Acceptable single screening test for CD Reflex pattern – positive screen results reflex to IgA and IgG antibody testing for tTG and DGP More expensive than tTG testing
Tissue Transglutaminase (tTG) Antibody IgA 0097709

Tissue Transglutaminase (tTG) Antibody IgG0056009

Recommended single screening test for CD
  • IgA testing recommended first to identify IgA deficiency prior to choosing tTG test

Use tTG IgA in individuals who are IgA-competent; use tTG IgG in individuals who are IgA-deficient

Confirmation by EMA may be necessary for low to moderate levels of tTG antibody

Testing for DGP antibodies may also increase sensitivity for CD, particularly in children <2 yrs

May be less reliable in children <2 yrs

tTG antibodies may be present despite undetectable levels of IgA

Deamidated Gliadin Peptide (DGP) Antibody, IgA 0051357

Deamidated Gliadin Peptide (DGP) Antibody,IgA 0051359

Acceptable single screening test for CD
  • IgA testing recommended first to identify IgA deficiency prior to choosing DGP test

May be considered in children <2 yrs if tTG or EMA negative

Higher sensitivity/specificity than conventional antigliadin antibody (AGA) tests

May be present in the absence of  tTG IgA antibodies
Endomysial Antibody, IgG 2005501

Endomysial Antibody, IgA by IFA 0050736

Acceptable single screening test for CD
  • IgA testing recommended first to identify IgA deficiency prior to choosing EMA  test

High clinical specificity with good positive predictive value for active CD

More labor intensive  and expensive than tTG or IgA/ IgG testing
aAll linked tests are available from ARUP Laboratories.
  • Initial testing
    • Serum IgA level by nephelometry – determination of IgA levels prior to antibody testing is recommended; if patient is IgA deficient, all serologic testing must be performed using IgG tests to prevent false-negative antibody results
      • IgA level ≥7.0 mg/dL but below age-matched range – order Celiac Dual Antigen Screen with Reflex (see table above for components and characteristics)
      • IgA <7.0 mg/dL – order tTG IgG and DGP IgG
        • Consider evaluation for immunoglobulin deficiency if IgG is normal – IgA deficiency may accompany other immunoglobulin deficiencies
        • Note – infants may present with transient suboptimal levels of IgA and/or IgG levels, which may not be related to immune deficiency
      • IgA level normal (age-matched range) – order tTG IgA
  • Other testing
    • F-actin IgA antibody by ELISA
      • Presence of anti-actin antibodies in biopsy-confirmed CD patients may indicate intestinal villus atrophy – more severe form of disease expected
      • Should be ordered only in patients with confirmed CD by biopsy

Histology

Prognosis

  • Anti-actin IgA (F-actin)
    • Levels correlate with severity of mucosa damage
    • May indicate moderate to severe disease – lacks specificity

Differential Diagnosis

  • General differential based on clinical presentation
  • Villous atrophy on biopsy
    • Tropical sprue
    • Whipple disease
    • Small intestinal bowel overgrowth
    • Hypogammaglobulinemic sprue
    • Drug-associated enteropathy
    • Lactose intolerance
    • Crohn disease
    • Autoimmune enteropathy
    • Refractory sprue
    • Collagenous sprue
    • Radiochemotherapy
    • Graft-versus-host disease
    • Nutritional deficiencies
    • Enteropathy-induced T-cell lymphoma
  • Lymphocytic duodenosis
    • Helicobacter pylori
    • Medication effects
    • Small intestinal bowel overgrowth
    • Systemic autoimmune disorders
    • Intestinal lymphoma
    • Nonceliac gluten sensitivity

 

  • Insufficient evidence to recommend screening for celiac disease (CD) in asymptomatic population (USPSTF, 2017)
  • Serologic screening for CD is recommended for specific at-risk groups, including first-degree relatives of CD patients and individuals who have the following (ACG, 2013)
  • For asymptomatic at-risk children (groups referred to above) (ESPGHAN, 2012)
    • Screening should begin after 2 years AND
    • When child has been on wheat diet for ≥1 year OR
    • When suggestive signs and symptoms are present
  • Monitor therapeutic response to change in diet and patient compliance
    • tTG and/or DGP IgA or IgG assay, EMA assay
      • Assay should be chosen (IgA or IgG) based on IgA levels
      • Either tTG, DGP, or EMA assays can be used depending on previous results in monitoring adherence to gluten-free diet (GFD)
      • Typically ordered every 3-6 months – if levels remain elevated after >12 months of GFD, consider rebiopsy
      • Decline in antibody levels may correlate with normalization of the intestinal villi
    • F-actin IgA antibody
      • Strict adherence to GFD and normalization of the intestinal villi correlate with declining levels of F-actin IgA antibodies in some patients with celiac disease

Celiac disease (CD), or gluten sensitive enteropathy, is a nonallergic, immune-mediated sensitivity (in genetically susceptible individuals) to gluten or related proteins.

Epidemiology

  • Incidence – approximately 1/141 in the U.S. (Rubio-Tapia, 2012)
  • Age – three peaks
    • Infancy
    • Second to third decade of life
    • Fifth to sixth decade of life
  • Sex – M<F,  1:1.3 (Rubio-Tapia, 2012)
  • Ethnicity
    • CD risk varies between ethnicities and geographic regions, suggesting that environmental and/or lifestyle risk factors may play a role in disease etiology

Genetics

  • HLA-DQ2 (encoded by HLA-DQA1*05 and HLA-DQB1*02) – 90-95% of CD patients have HLA-DQ2
  • HLA-DQ8 (encoded by HLA-DQB1*03:02) – 5-10% of CD patients have HLA-DQ8
  • 75-90% concordance in monozygotic twins; 10-20% in dizygotic twins

Risk Factors

Pathophysiology

  • T-cell mediated inflammatory response in proximal small bowel
    • Celiac lesion may be characterized by increased intraepithelial lymphocytes with crypt hyperplasia and partial, subtotal, or total villous atrophy
  • Tissue transglutaminase (tTG) has been identified as the major target autoantigen of the endomysial antibody (EMA)
    • tTG is an enzyme that catalyzes the replacement of amide groups of protein and peptide-bound glutamine residues by primary amines (cross-linking) as well as by hydrolysis (deamidation)
  • Gliadin, a glutamine-rich protein, has been identified as a specific substrate for tTG

Clinical Presentation

  • Clinical presentation – varied; tends to differ by age group
  • Children and adolescents 
    • Gastroenterological symptoms (diarrhea, abdominal pain, bloating)
    • Poor growth
    • Delayed puberty
    • Iron deficiency anemia
    • Abnormal liver testing
  • Adults
    • Gastrointestinal symptoms (diarrhea, abdominal pain, bloating)
    • Unexplained iron deficiency
    • Dermatitis herpetiformis
    • Early-onset osteoporosis
    • Delayed puberty/unexplained short stature
    • Family history of CD
    • Extraintestinal symptoms
      • Fatigue and malaise – may occur independently of anemia
      • Neurologic or psychiatric disorders – epilepsy, depression, migraines
      • Musculoskeletal disorders – osteopenia, osteoporosis,  joint pain/inflammation
      • Infertility/recurrent fetal loss
      • Mouth ulcers/dermatitis herpetiformis
    • Associated autoimmune conditions

 

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Celiac Disease Reflexive Cascade 2008114
Method: Quantitative Nephelometry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay//Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

​Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

At screening dilution, EMA may show prozone phenomenon; if suspicion for disease is strong, consider testing for tTg and/or DGP antibodies

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease 

Tissue Transglutaminase (tTG) Antibody, IgA 0097709
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Tissue Transglutaminase Antibody, IgG 0056009
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Deamidated Gliadin Peptide (DGP) Antibody, IgA 0051357
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Deamidated Gliadin Peptide (DGP) Antibody, IgG 0051359
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Endomysial Antibody, IgA by IFA 0050736
Method: Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

At screening dilution, EMA may show prozone phenomenon; if suspicion for disease is strong, consider testing for tTg and/or DGP antibodies

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Endomysial Antibody, IgG 2005501
Method: Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

At screening dilution, EMA may show prozone phenomenon; if suspicion for disease is strong, consider testing for tTg and/or DGP antibodies

Sera containing anti-smooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG

Sera should be further tested at higher dilutions

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Celiac Disease Dual Antigen Screen with Reflex 2002026
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

Celiac Disease Dual Antigen Screen 0051689
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Correlation between CD serologic tests may be variable at low antibody titers, early disease, or treatment with GFD; strong clinical correlation is recommended

False-negative results

  • Early disease
  • Individuals on GFD
  • Use of immunosuppression

False-positive results

  • Consider early disease and/or specific risk for CD

Small bowel biopsy and/or HLA DQ typing may be important in establishing a diagnosis of CD based on patient’s age, clinical symptoms, and/or risk for disease

F-Actin (Smooth Muscle) Antibody, IgA 0051724
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Not specific for CD

Does not replace intestinal biopsy for confirming CD

Celiac Disease (HLA-DQ2, and HLA-DQ8) Genotyping 2005018
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Rare diagnostic errors can occur due to primer-site mutations

Copy number of each detected allele will not be determined

Other HLA types will not be detected

Other genetic and nongenetic factors that influence CD are not evaluated

Guidelines

Giersiepen K, Lelgemann M, Stuhldreher N, Ronfani L, Husby S, Koletzko S, Korponay-Szabó IR, ESPGHAN Working Group on Coeliac Disease Diagnosis. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J Pediatr Gastroenterol Nutr. 2012; 54(2): 229-41. PubMed

Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP, ESPGHAN Working Group on Coeliac Disease Diagnosis, ESPGHAN Gastroenterology Committee, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012; 54(1): 136-60. PubMed

Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006; 131(6): 1981-2002. PubMed

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; 108(5): 656-76; quiz 677. PubMed

US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Barry MJ, Davidson KW, Doubeni CA, Ebell M, Epling JW, Herzstein J, Kemper AR, Krist AH, Kurth AE, Landefeld S, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng C. Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2017; 317(12): 1252-1257. PubMed

World Gastroenterology Organisation Global Guidelines - Celiac Disease. World Gastroenterology Organisation. Milwaukee, WI [Accessed: Apr 2017]

General References

Brusca I. Overview of biomarkers for diagnosis and monitoring of celiac disease. Adv Clin Chem. 2015; 68: 1-55. PubMed

Caja S, Mäki M, Kaukinen K, Lindfors K. Antibodies in celiac disease: implications beyond diagnostics. Cell Mol Immunol. 2011; 8(2): 103-9. PubMed

Crowe SE. In the clinic. Celiac disease. Ann Intern Med. 2011; 154(9): ITC5-1-ITC5-15; quiz ITC5-16. PubMed

Ensari A. Gluten-sensitive enteropathy (celiac disease): controversies in diagnosis and classification. Arch Pathol Lab Med. 2010; 134(6): 826-36. PubMed

Harrison MS, Wehbi M, Obideen K. Celiac disease: more common than you think. Cleve Clin J Med. 2007; 74(3): 209-15. PubMed

Jenkins HR, Murch SH, Beattie RM, Coeliac Disease Working Group of British Society of Paediatric Gastroenterology, Hepatology and Nutrition. Diagnosing coeliac disease. Arch Dis Child. 2012; 97(5): 393-4. PubMed

Lebwohl B, Ludvigsson JF, Green PH. Celiac disease and non-celiac gluten sensitivity. BMJ. 2015 Oct 5;351:h4347. Review. PubMed

Plebani M, Basso D. Diagnostic testing for celiac disease. JAMA. 2010; 304(6): 639; author reply 639-40. PubMed

Prause C, Richter T, Koletzko S, Uhlig H, Hauer AC, Stern M, Zimmer K, Laass MW, Probst C, Schlumberger W, Mothes T. New developments in serodiagnosis of childhood celiac disease: assay of antibodies against deamidated gliadin. Ann N Y Acad Sci. 2009; 1173: 28-35. PubMed

Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012; 107(10): 1538-44; quiz 1537, 1545. PubMed

Sugai E, Hwang HJ, Vázquez H, Smecuol E, Niveloni S, Mazure R, Mauriño E, Aeschlimann P, Binder W, Aeschlimann D, Bai JC. New serology assays can detect gluten sensitivity among enteropathy patients seronegative for anti-tissue transglutaminase. Clin Chem. 2010; 56(4): 661-5. PubMed

van der Windt DA, Jellema P, Mulder CJ, Kneepkens CM, van der Horst HE. Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review. JAMA. 2010; 303(17): 1738-46. PubMed

Vermeersch P, Coenen D, Geboes K, Mariën G, Hiele M, Bossuyt X. Use of likelihood ratios improves clinical interpretation of IgA anti-tTG antibody testing for celiac disease. Clin Chim Acta. 2010; 411(1-2): 13-7. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Jaskowski TD, Hamblin T, Wilson AR, Hill HR, Book LS, Meyer LJ, Zone JJ, Hull CM. IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis and pediatric celiac disease. J Invest Dermatol. 2009; 129(11): 2728-30. PubMed

Jaskowski TD, Schroder C, Martins TB, Litwin CM, Hill HR. IgA antibodies against endomysium and transglutaminase: a comparison of methods. J Clin Lab Anal. 2001; 15(3): 108-11. PubMed

Nandiwada SL, Tebo AE. Testing for antireticulin antibodies in patients with celiac disease is obsolete: a review of recommendations for serologic screening and the literature. Clin Vaccine Immunol. 2013; 20(4): 447-51. PubMed

Patil DT, Bennett AE, Mahajan D, Bronner MP. Distinguishing Barrett gastric foveolar dysplasia from reactive cardiac mucosa in gastroesophageal reflux disease. Hum Pathol. 2013; 44(6): 1146-53. PubMed

Medical Reviewers

Content Reviewed: 
April 2017

Last Update: September 2017