Celiac Disease

Diagnostic Algorithm

  Celiac Disease or Gluten Sensitive Enteropathy Testing Algorithm

Clinical Background

Celiac disease or gluten sensitive enteropathy is a non-allergic, 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 – median is 20s
• Ethnic – mainly affects Caucasians of North European ancestry

Risk Factors

• HLA-DQ2 allele (90-95%)
• HLA-DQ8 (5-10%)
• 75% concordance in monozygotic twins

Pathophysiology

• Inappropriate immune response to gluten in wheat or related proteins in barley and rye
• 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
      • Short stature
      • Anemia
      • 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
• Associated conditions
  • Dermatitis herpetiformis
  • IgA deficiency
  • Increased risk of lymphoma

Treatment

• Gluten-free diet may control celiac disease/gluten sensitive enteropathy and associated risks

Diagnosis

Indications for Testing

• Chronic diarrhea without infectious etiology
• Family history of celiac disease
• Early-onset osteoporosis
• Autoimmune disease associated with celiac disease (type I diabetes, autoimmune thyroiditis, etc.)
• Non-autoimmune conditions associated with celiac disease (Down syndrome, Turner syndrome, etc.)

Criteria for Diagnosis

• Positive tTG IgA or EMA serologic test
• Positive tissue biopsy
• 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

• Testing necessary to determine if IgA or IgG antibody testing is correct
  • Serum IgA level by nephlometry
    • If IgA deficiency is suspected, determination of IgA levels prior to antibody testing is recommended
    • If patient is IgA deficient, all antibody testing will need to be performed using IgG tests to prevent under-diagnosis of celiac disease
      • If IgA is deficient and IgG is normal, consider evaluation for immunoglobulin deficiency
      • If testing infants between 5-6 months, it should be noted that there is a period of transient hypogammaglobinemia, so infants can appear IgA/IgG deficient without being so
• tTG antibodies IgA by ELISA
  • Has been reported to have equivalent diagnostic utility as EMA IgA by IFA for celiac disease
  • Sensitivity and specificity about 98%
• Deaminated gliadin peptide (DGP) antibodies IgA by ELISA
  • Higher sensitivity/specificity than conventional antigliadin antibody tests
  • May be present without tTG IgA antibodies
  • In some cases, tTG and/or deamidated gliadin IgG antibodies may be present despite detectable levels of IgA
  • If suspicion for celiac disease is strong and tTG IgA is negative, the presence of tTG IgG and DPG (IgA and IgG) antibodies may be clinically relevant
• Celiac disease dual-antigen screen with reflex by ELISA
  • May be clinically useful in individuals with selective IgA deficiency or suboptimal IgA levels
• F-Actin IgA antibody by ELISA
  • Presence of anti-Actin antibodies in biopsy-confirmed celiac disease patients may indicate intestinal villus atrophy
  • Should be ordered only in patients with confirmed celiac disease by biopsy
• HLA typing
  • Not necessary for routine laboratory evaluation of celiac disease because of its low positive predictive value
  • May be indicated in individuals at risk for celiac disease or individuals who are repeatedly seropositive but biopsy-negative
  • The absence of HLA-DQ2 or -DQ8 eliminates the risk for celiac disease

Histology

• Duodenal biopsy – gold standard for celiac disease diagnosis
  • 4 or 5 samples should be taken to increase probability
  • Intestinal damage is assessed by a modified Marsh score
    • Scores range from 0, 1, 2, 3a to 3c
    • Only Marsh scores 2 and above are considered clinically significant
  • Patient should not be on a gluten-free diet at time of biopsy

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
• Inflammatory bowel disease
• Malabsorption
• Malnutrition
• Colorectal cancer

Screening

Monitoring

Indications for Laboratory Testing

• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Reticulin Antibody, IgA with Reflex to Titer 0050698 Method: Indirect Fluorescent Antibody	Not recommended for celiac disease testing; use tTG testing
Reticulin Antibody, IgG with Reflex to Titer 0098878 Method: Indirect Fluorescent Antibody	Not recommended for celiac disease testing; use tTG testing
Immunoglobulin A, Serum 0050340 Method: Nephelometry	IgA results determine whether to use IgA or IgG tTG and DGP assays
Tissue Transglutaminase (tTG) Antibody, IgA with Reflex to Endomysial Antibody, IgA Titer by IFA 0050734 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody	Screen for celiac disease in patients who are not IgA deficient Certain individuals, particularly children <3 years who test negative for tTG and/or EMA antibodies, may be positive for DGP IgA and/or IgG antibodies tTG IgA and EMA IgA have equivalent diagnostic utility for celiac disease
Deamidated Gliadin Peptide (DGP) Antibodies, IgA & IgG 0051358 Method: Enzyme-Linked Immunosorbent Assay	Certain individuals, particularly children <3 years who test negative for tTG and/or EMA antibodies, may be positive for DGP IgA and/or IgG antibodies Test results alone are not diagnostic; biopsy recommended for a diagnosis of celiac disease/gluten sensitive enteropathy