Celiac Disease in Children and Adolescents

Recent guidelines from the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) discuss serology testing for the evaluation of celiac disease (CD) and suggest when HLA-DQ2/HLA-DQ8 typing is recommended.

For details on ESPGHAN’s recommendations for CD testing in children and adolescents, see the table below.

Indications for Testing

• Symptomatic patient
  • Typical gastrointestinal manifestations of celiac disease (CD)
    • Chronic or intermittent diarrhea without infectious etiology
    • Failure to thrive in children
  • Atypical extraintestinal symptoms
    • Unexplained iron deficiency
    • Dermatitis herpetiformis
    • Early-onset osteoporosis
    • Delayed puberty/unexplained short stature
• Asymptomatic (at-risk) patient
  • Family history of CD
  • Syndromes associated with risk for CD (eg, Down syndrome, Turner syndrome)
  • Autoimmune disease associated with CD (eg, diabetes mellitus type 1, thyroid or adrenal disease)

Criteria for Diagnosis

• Positive tTG IgA and/or EMA IgA serologic test with biopsy consistent with CD in individuals with normal serum IgA levels
  • CD may be confirmed without the need for biopsy in symptomatic individuals with high levels of CD-specific antibodies and who are HLA-DQ2/DQ8 positive
• Complete resolution of clinical symptoms and/or a seronegative response following a gluten-free diet
  • Gluten rechallenge not necessary except in patients who had no initial biopsy or an uncharacteristic biopsy

Laboratory Testing

• Celiac disease tests and characteristics

  Test	Characteristics	Limitations
  Celiac Disease Reflexive Panel (includes IgA, tTG antibodies and DGP antibodies)	Preferred reflexive screening panel for celiac disease (CD) diagnosis Reflexes to tTG IgA or IgG based on IgA level
  Celiac Dual Antigen Screen with Reflex (includes tTG IgA/IgG by ELISA; DGP IgA/IgG by ELISA)	Acceptable reflexive screening test for CD	More expensive than tTG testing
  Tissue Transglutaminase Antibody (tTG) IgA/IgG by ELISA	Preferred single initial screen for CD due to increased sensitivity, lack of subjectivity Confirmation by endomysial antibody (EMA) may be necessary for low to moderate levels of tTG antibody results Testing for deamidated gliadin peptide (DGP) antibodies may also increase sensitivity for CD, particularly in children <2 years	May be less reliable in children <2 years tTG antibodies may be present despite undetectable levels of IgA
  Deamidated Gliadin Peptide (DGP) IgA/IgG by ELISA	Not a recommended first line test for CD May be considered in children <2 years 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 (EMA) IgA/IgG by IFA	Acceptable screen for CD High clinical specificity with good positive predictive value for active CD Testing for DGP antibodies may improve diagnostic sensitivity in children <2 years May be used as an alternate to EMA to confirm low to moderate tTG antibody results	More labor intensive  and expensive than tTG IgG testing

• Initial testing
  • Serum IgA level by nephelometry – for determination of IgA levels prior to antibody testing (recommended); if patient is IgA deficient, all serologic testing must be performed with 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 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 ≥100 U)	Celiac disease (CD) likely; consider HLA genotyping (see Genetic testing)
        Weak-moderate positive tTG IgA (20-99 U)	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 (<19 U)	CD unlikely Exclude history of gluten-free diet or immunosuppressants (causes false-positive results) Consider HLA genotyping (in light of age and associated diseases) – refer to Genetic Testing section

• Genetic testing – HLA genotyping
  • HLA-DQ2 (HLA-DQA1*05 and HLA-DQB1*02) and HLA-DQ8 (HLA-DQB1*03:02)
    • HLA-DQ2 is positive in 90-95% of patients; presence does not confirm CD
    • Found in 30-40% of general population
    • Absence virtually excludes CD
    • Not necessary for routine laboratory evaluation of CD because of its low positive predictive value
    • May be indicated in individuals at risk for CD or individuals who are repeatedly seropositive but biopsy-negative
    • Wheat allergy testing – do not order because it is not relevant
  • Results
    • HLA positive – CD confirmed
      • Not necessary to confirm by biopsy; may consider biopsy for atypical presentation
    • HLA negative – likely false-positive tTG test
• 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

• Duodenal biopsy – gold standard for CD diagnosis
  • 4-5 samples should be taken to increase probability
  • Patient should not be on a gluten-free diet at time of biopsy
  • Intestinal damage is assessed by a modified Marsh score
    • Scores range from 0, 1, 2, 3a to 3c
    • Marsh 0-1
      • Consider early phase disease
      • Follow-up testing on normal diet
      • Consider false-positive results
    • Marsh ≥2
      • CD confirmed

Prognosis

• Anti-actin IgA (F-actin) levels correlate with severity of mucosa damage and may indicate moderate to severe disease

Differential Diagnosis

• Irritable bowel syndrome (IBS)
• Inflammatory bowel disease
• Malabsorption
• Malnutrition
• Colorectal cancer
• Lactose intolerance
• Microscopic colitis
• Other carbohydrate intolerance
• Eosinophilic gastroenteritis
• Infectious – Giardia
• Intestinal lymphoma
• Pancreatic insufficiency
• Common variable immune deficiency
• Autoimmune enteropathy
• IgA deficiency

• Serologic and/or genetic (HLA-DQ2 and HLA-DQ8) screening is not recommended for the general population

• Serologic screening for celiac disease (CD) is recommended for specific at-risk groups, including first degree relatives of CD patients and individuals with the following
  • Type 1 DM
  • Autoimmune thyroid disease
  • IBS
  • Dermatitis herpetiformis
  • Down syndrome
  • Turner syndrome
  • Williams syndrome
  • Selective IgA deficiency
• For asymptomatic at-risk children (groups referred to above) screening  should begin after 2 years and when child has been on wheat diet for ≥1 year or with suggestive signs and symptoms
• HLA-DQ2 and HLA-DQ8 testing is recommended mostly for exclusion when diagnostic and biopsy results are equivocal  
  • In rare cases, some patients with CD have been reported to have only DQA1*05 or DQB1*02, the latter usually associated with HLA-DR7 heterozygosity or homozygosity

• Monitoring adherence to gluten-free diet (GFD) or disease activity is part of American Gastroenterological Association (AGA) guidelines
  • tTG and/or DGP IgA and IgG assays
    • Either tTG or DGP assays can be used depending on previous results in monitoring adherence to GFD
    • Assay should be chosen (IgA or IgG) based on IgA levels
    • Decline in antibody levels may correlate with normalization of the intestinal villi
    • Typically ordered every 3-6 months – if levels remain elevated after >12 months of GFD, consider rebiopsy
  • 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 in wheat or related proteins found in barley and rye.

Epidemiology

• Incidence – 1/100-150 in the U.S.
• Age – three defined peaks
  • Infancy
  • Second to third decade of life
  • Fifth to sixth decade of life
• Ethnicity – mainly affects Caucasians of European origin

Genetics

• HLA-DQ2 (HLA-DQA1*05 and HLA-DQB1*02) – 90-95% of CD patients have HLA-DQ2
• HLA-DQ8 (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)
• Autoimmune disorders associated with risk for CD (eg, Addison disease, diabetes mellitus type 1, Sjögren syndrome, autoimmune thyroid 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 atrophy
• tTG (tissue transglutaminase) 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
  • Deamidation of gliadin has been reported to improve the overall diagnostic performance of conventional antigliadin antibody assays

Clinical Presentation

• Clinical presentation is extremely varied and tends to differ by age group
  • General symptoms – anemia, fatigue, weight loss
  • Pediatric symptoms – diarrhea, abdominal distention, malnutrition
    • Symptoms of malnutrition include the following
      • Short stature
      • Anemia (typically iron deficient)
      • Defects in dentition
      • Failure to thrive
      • Developmental delay
  • Adult symptoms – abdominal pain, flatulence, diarrhea, steatorrhea in severe cases
    • Extraintestinal symptoms
      • Fatigue and malaise (may occur independently of anemia)
      • Neurologic or psychiatric disorders
      • Neuromuscular abnormalities
      • Infertility
      • Mouth ulcers
      • Recurrent fetal loss
• Associated conditions
  • Osteopenic bone disease
  • Small-for-gestational-age infants
  • Dermatitis herpetiformis – symptoms of malabsorption may be absent
  • IgA deficiency
  • Increased risk of lymphoma
  • Other autoimmune disorders
    • Type 1 diabetes mellitus (DM)
    • Autoimmune thyroid disease
    • Autoimmune adrenal disease
    • Sjögren syndrome
    • Rheumatoid arthritis
    • Systemic lupus erythematosus
    • Primary biliary cirrhosis
    • Primary sclerosing cholangitis
    • Inflammatory bowel disease (IBD)
  • Higher risk in patients with Down or Turner syndrome

Treatment

• Gluten-free diet may control celiac disease/gluten sensitive enteropathy and associated risks
  • Positive predictive value of benefits of gluten-free diet <40%
  • Response does not equate to disease being present
  • Gluten-free diet removes other components that make symptoms worse in IBD, functional dyspepsia, or gastroesophageal reflux disease
• American Gastroenterological Association (AGA) recommends lifelong adherence to gluten-free diet if celiac confirmed
• 5% are true nonresponders to diet (refractory celiac disease)
  • Consider immunosuppressive therapy to reduce risk of lymphoma

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Coeliac disease. Recognition and assessment of coeliac disease. National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]. 2009 May. NGC:007538
• Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012; 54 (1) :136-160.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

General

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ARUP Institute for Clinical and Experimental Pathology®

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Diarrhea, Bacterial Evaluation
Diarrhea, Parasitic Evaluation
Diarrhea, Viral Evaluation
Food Allergies
Inflammatory Bowel Disease
Malabsorption
Osteoporosis