Celiac Disease

Celiac disease (CD), or gluten sensitive enteropathy, is a nonallergic, immune-mediated sensitivity (in genetically susceptible individuals) to gluten or related proteins. While biopsy is the gold standard for CD diagnosis, initial testing typically includes assessing serum IgA level and then proceeding with the appropriate tissue transglutaminase (tTG) antibody test (IgA or IgG, depending on whether or not the patient is IgA deficient).

Tabs Content

Clinical Overview

Key Points

Celiac Disease in Children and Adolescents

Guidelines from the European Society for Paediatric 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) Autoimmune disorders – type 1 diabetes mellitus, autoimmune thyroiditis, autoimmune liver disease At risk genetic syndromes – Down syndrome, Turner syndrome, Williams syndrome First-degree relatives with CD Selective IgA deficiency
Laboratory Testing Options
Recommended antibody tests Individual must be on gluten-containing diet when tested and IgA status must be known	tTG IgA is recommended single screening test Adding EMA IgA testing in high-probability individuals increases sensitivity In children <2 yrs with high suspicion of CD – consider anti-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	Celiac Disease Reflexive Cascase 2008114 (cascade begins with IgA and, depending on findings, 1 or more reflexive tests, including tTG IgA/IgG, EMA IgA, DGP IgA/IgG, and/or dual antigen screen, may be added) Individual IgA tests for IgA-competent individuals Tissue Transglutaminase (tTG) Antibody, IgA 0097709 Endomysial Antibody, IgA by IFA 0050736 Deamidated Gliadin Peptide (DGP) Antibody, IgA 0051357 Celiac Disease Dual Antigen Screen with Reflex 2002026 Celiac Disease Dual Antigen Screen 0051689 Individual IgG tests for IgA-deficient individuals Tissue Transglutaminase Antibody, IgG 0056009 Endomysial Antibody, IgG 2005501 Deamidated Gliadin Peptide (DGP) Antibody, IgG 0051359 Celiac Disease Dual Antigen Screen with Reflex 2002026 Celiac Disease Dual Antigen Screen 0051689 Should not routinely be performed Celiac Disease (HLA-DQ2, and HLA-DQ8) Genotyping 2005018
Husby, 2012 CD = celiac disease; DGP = deamidated gliadin peptide; EMA = endomysial antibody; ESPGHAN = European Society for Paediatric Gastroenterology, Hepatology and Nutrition; tTG = tissue transglutaminase

Diagnosis

Indications for Testing

Children and adolescents (European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN], 2012)
- Who have unexplained
  - Gastroenterological symptoms
  - Poor growth
  - Delayed puberty
  - Iron deficiency anemia
  - Abnormal liver testing
- Who have 1 of the following risks for celiac disease (CD) (even if asymptomatic)
  - Autoimmune disorders – type 1 diabetes mellitus, autoimmune thyroiditis, autoimmune liver disease
  - At risk genetic syndromes – Down syndrome, Turner syndrome, Williams syndrome
  - First-degree relatives with CD
  - Selective IgA deficiency
Adults
- Who have unexplained
  - Gastrointestinal symptoms (diarrhea, abdominal pain, bloating)
  - Unexplained iron deficiency
  - Dermatitis herpetiformis
  - Recurrent aphthous stomatitis
  - Early-onset osteoporosis
  - Delayed puberty/unexplained short stature
  - Alopecia areata
- Who have 1 of the following risks for CD (even if asymptomatic)
  - Family history of CD
  - Syndromes associated with risk for CD (eg, Down syndrome, Turner syndrome)
  - Autoimmune disease associated with CD (eg, type 1 diabetes mellitus, thyroid or adrenal disease)
  - Selective IgA deficiency

Criteria for Diagnosis

Positive tissue transglutaminase (tTG) IgA (American College of Gastroenterology [ACG], 2013) and/or endomysial antibody (EMA) IgA serologic test (ESPGHAN, 2012)
Biopsy consistent with celiac disease (CD) in individuals with normal serum IgA levels
tTG IgA or deamidated gliadin peptide (DGP) and biopsy, with HLA-DQ genotyping only in event of biopsy/serology disagreement (World Gastroenterology Organization [WGO], 2016)
CD may be confirmed without the need for biopsy in symptomatic individuals with high levels of CD-specific antibodies (10x 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
Test^a	Characteristics	Limitations
Celiac Disease Reflexive Cascade 2008114	Preferred reflex screening test for CD diagnosis Depending on initial results from IgA screening, ≥1 of the following tests may be added for clinical interpretation tTG antibody, IgA tTG antibody, IgG EMA, IgA by IFA DGP antibody, IgA DGP antibody, IgG CD dual antigen screen
Tissue Transglutaminase (tTG) Antibody IgA 0097709 Tissue Transglutaminase (tTG) Antibody IgG 0056009	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
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
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 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 AGA = antigliadin antibody; CD = celiac disease; DGP = deamidated gliadin peptide; EMA = endomysial antibody; tTG = tissue transglutaminase

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)

Celiac Dual Antigen Screen with Reflex test results

Celiac Disease Dual Antigen Screen with Reflex Test Results
Normal	Celiac disease unlikely
Positive or equivocal	Consider HLA genotyping (refer to Genetic testing section)

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
- tTG IgG and DGP IgG test results
  
  tTG IgG and DGP IgG Test Results
  Normal Celiac disease unlikely
  Positive or equivocal Consider HLA genotyping (refer to Genetic testing section)

IgA level normal (age-matched range) – order tTG IgA

tTG IgA test results

tTG IgA Test Results
High-positive tTG IgA (≥41 U/mL)	CD likely; consider HLA genotyping (see Genetic testing section)
Weak-moderate positive tTG IgA (4-40 U/mL)	Order EMA IgA by IFA, DGP IgA, HLA genotyping
EMA and/or DGP negative; HLA positive	Perform biopsy (see Histology section)
EMA and/or DGP positive, HLA negative	Likely false-negative HLA genotyping test; consider biopsy to confirm or rule out CD
EMA and/or DGP positive, HLA positive	CD confirmed
EMA and DGP negative; HLA negative	Likely false-positive anti-tTG test
Negative tTG IgA (≤3 U/mL)	CD unlikely Exclude history of gluten-free diet or immunosuppressive drug (causes false-positive results) Consider HLA genotyping (in light of age and associated diseases) – refer to Genetic Testing section
CD = celiac disease; DGP = deaminated gliadin peptide; EMA = endomysial antibody; tTG = tissue transglutaminase

Genetic testing

HLA genotyping – HLA-DQ2 (encoded by HLA-DQA1*05 and HLA-DQB1*02) and HLA-DQ8 (encoded by HLA-DQB1*03:02)
- DQ2
  - Present in >90% of individuals with celiac disease (CD); presence does not confirm CD
  - Found in 20-30% of general population
- DQ8
  - Present in ~5-10% of individuals with CD
  - Found in 10% of general population
- Absence virtually excludes CD
- Not necessary for routine laboratory evaluation of CD due to low positive predictive value
- May be indicated in individuals at risk for CD or individuals who are repeatedly seropositive but biopsy negative
- Biopsy can be avoided if IgA anti-tTg >10x manufacturer's cutoff, confirmed by endomysial antibodies (EMA) in a different blood sample, and HLA testing is positive (ESPGHAN, 2012)

Other testing – F-actin IgA antibody by enzyme-linked immunosorbent assay (ELISA)
- Presence of antiactin 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

Duodenal biopsy – gold standard for CD diagnosis
- 4-5 samples preferred to increase probability – ≥1 from the bulb and ≥4 from the second and third portion of the duodenum (ESPGHAN, 2012)
- Patient must be on a gluten-containing diet at time of biopsy
Intestinal damage is indicated by modified Marsh classification of histologic findings in CD (Oberhuber) or simplified system classification (Corazza, Roberts, Ensari)

Prognosis

Antiactin 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
- Irritable bowel syndrome
- Inflammatory bowel disease
- Infectious
  - Giardia
  - Cryptosporidium
  - Mycoplasma tuberculosis
- Common variable immune deficiency
- Malabsorption
- Colorectal cancer
- Malnutrition
- Wheat allergy
- Nongluten food hypersensitivity
- Nonceliac gluten sensitivity
- Microscopic colitis
- Eosinophilic gastroenteritis
- Intestinal lymphoma
- Pancreatic insufficiency
- IgA deficiency
- Small intestinal bowel overgrowth
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

Screening

Insufficient evidence to recommend screening for celiac disease (CD) in asymptomatic population (U.S. Preventive Services Task Force [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 (American College of Gastroenterology [ACG], 2013)
- Autoimmune disorders
- Genetic disorders – Down, Turner, and Williams syndromes
- Selective IgA deficiency
For asymptomatic at-risk children (groups referred to above), begin screening (European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN], 2012)
- After 2 years AND when child has been on wheat-containing diet for ≥1 year OR
- When suggestive signs and symptoms are present

Monitoring

Monitor therapeutic response to change in diet and patient compliance
- Tissue transglutaminase (tTG) and/or deaminated gliadin peptide (DGP) IgA or IgG assay, endomysial antibody (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

Background

Epidemiology

Incidence – approximately 1/141 in the U.S. (Rubio-Tapia, 2012)
Age – 3 peaks
- Infancy
- Second to third decade of life
- Fifth to sixth decade of life
Sex – M<F, 1:1.3 (Rubio-Tapia, 2012)
Ethnicity – celiac disease (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

Family history (eg, first-degree relative with CD)
Syndromes associated with risk for CD (eg, Down syndrome, Turner syndrome, Williams syndrome)
Autoimmune disorders associated with risk for CD (eg, autoimmune adrenal disease, type 1 diabetes mellitus [T1DM], Sjögren syndrome, autoimmune thyroid disease, autoimmune liver disease)
Immune deficiencies (eg, IgA deficiency)
Dermatitis herpetiformis

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
  - T1DM
  - Autoimmune thyroid disease
  - Autoimmune adrenal disease
  - Sjögren syndrome
  - Rheumatoid arthritis
  - Systemic lupus erythematosus
  - Primary biliary cirrhosis
  - Primary sclerosing cholangitis
  - Inflammatory bowel disease (IBD)

ARUP Lab Tests

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

Recommended Use

Preferred reflexive screening test for celiac disease (CD)

Depending on initial results from IgA screening, 1 or more of the following tests may be added for clinical interpretation

Tissue transglutaminase (tTG) antibody, IgA
tTG antibody, IgG
Endomysial antibody (EMA), IgA by indirect fluorescent antibody (IFA)
Deamidated gliadin peptide (DGP) antibody, IgA
DGP antibody, IgG
CD dual antigen screen

May aid in monitoring adherence to gluten-free diet (GFD)

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Recommended single screening test for IgA-competent individuals with suspected CD

IgA testing recommended to identify IgA competence prior to choosing tTG test

May aid in monitoring adherence to GFD in CD-confirmed patients

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Recommended single screening test for IgA-deficient individuals with suspected CD

IgA testing recommended to identify IgA deficiency prior to choosing tTG test

May aid in monitoring adherence to GFD in CD-confirmed patients

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Acceptable reflexive screening test for CD

Screen includes tTG antibodies IgA and IgG, and DGP antibodies IgA and IgG

CD reflexive cascade or tTG IgA tests preferred for screening patients with suspected CD

Reflex pattern – positive screen reflexes to IgA antibody testing for tTG and DGP; negative IgA testing for tTG and DGP reflexes to IgG antibody testing for tTG and DGP

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Acceptable single screening test for IgA-competent individuals with suspected CD

IgA testing recommended to identify IgA deficiency prior to choosing DGP test

May be useful in diagnosing children <2 years who test negative for tTG and EMA antibodies

May aid in monitoring adherence to GFD

CD reflexive cascade or tTG antibody, IgA is the preferred test for screening patients with suspected CD

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Acceptable single screening test for IgA-deficient individuals with suspected CD

IgA testing recommended to identify IgA deficiency prior to choosing DGP test

May be useful in diagnosing children <2 years who test negative for tTG and EMA antibodies

May aid in monitoring adherence to GFD

CD reflexive cascade or tTG antibody, IgA is the preferred test for screening patients with suspected CD

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Acceptable single screening test for IgA-competent individuals with suspected CD

IgA testing recommended to identify IgA competence prior to choosing EMA test

Preferred screening test for individuals with suspected CD is CD reflexive cascade or tTG, IgA

EMA IgA is acceptable follow-up test for weakly positive or negative tTg IgA screen

May aid in monitoring adherence to GFD in CD-confirmed patients

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Acceptable single screening test for IgA-deficient individuals with suspected CD

IgA testing recommended to identify IgA deficiency prior to choosing EMA test

Preferred screening test is CD reflexive cascade or tTG, IgG

May aid in monitoring adherence to GFD in CD-confirmed patients

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 antismooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG

Sera should be further tested at higher dilutions

False-negative results may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Acceptable single screening test for CD

Screen includes tTG antibodies IgA and IgG, and DGP antibodies IgA and IgG

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 may occur in early disease, in individuals on GFD, and with 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

Recommended Use

Do not use to screen for CD

May be used to estimate severity of intestinal villous atrophy in confirmed CD

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

Recommended Use

Do not use in initial evaluation of CD

Useful in ruling out CD (high negative predictive value) in selective clinical situations such as

Equivocal small bowel histologic finding (Marsh I-II) in seronegative individuals
Evaluation of individuals on a GFD in whom no testing for CD was done before GFD
Individuals with discrepant celiac-specific serology and histology
Strong serologic evidence and clinical suspicion, and desire to avoid small bowel biopsy (eg, children)

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

Medical Reviewers

Delgado, Julio, MD, MS, Chief Medical Officer; Director of Laboratories; Chief, Division of Clinical Pathology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Miller, Christine E., MS, LCGC, Genetic Counselor, Molecular Genetics at ARUP Laboratories; Faculty, Graduate Program in Genetic Counseling, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

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: Jan 2018]

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

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

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

Testing Algorithms

Celiac Disease Testing for Symptomatic Individuals Algorithm

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January 2018

Last Update: March 2018


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	Tebo A. Celiac Disease. ARUP Consult^©. Retrieved April 18, 2018, from: https://arupconsult.com/content/celiac-disease

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Celiac Disease

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Key Points

Celiac Disease in Children and Adolescents

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Prognosis

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Genetics

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

Celiac Disease Testing for Symptomatic Individuals Algorithm

References from the ARUP Institute for Clinical and Experimental Pathology^®