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
• Ethnicity – mainly affects Caucasians of North European ancestry

Risk Factors

• HLA-DQ2 (HLA-DQA1*05 and HLA-DQB1*02) allele – 90-95%
• HLA-DQ8 (HLA-DQB1*03:02) – 5-10%
• 75% concordance in monozygotic twins

Pathophysiology

• 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
      • 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

Indications for Testing

• Chronic diarrhea without infectious etiology
• Family history of celiac disease
• Early-onset osteoporosis
• Autoimmune disease associated with celiac disease (diabetes mellitus type 1, autoimmune thyroiditis, etc)
• Non-autoimmune conditions associated with celiac disease (Down syndrome, Turner syndrome, etc)

Criteria for Diagnosis

• Positive tTG IgA and/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

• Determination of IgA deficiency status is important in celiac serologic testing
  • Serum IgA level by nephelometry
    • 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 false-negative antibody results
      • If IgA is deficient and IgG is normal, consider evaluation for immunoglobulin deficiency
      • Infants may present with transient sub-optimal levels of IgA and/or IgG levels, which may not be related to immune deficiency
• tTG antibodies IgA/IgG by ELISA
  • Due to the increased sensitivity and lack of subjectivity of the tTG ELISAs, they are the preferred single initial screening tools for celiac disease
• EMA IgA/IgG by IFA
  • EMA IgA/IgG by IFA has high clinical specificity with good positive predictive value for active celiac disease
  • Confirmation with EMA is advised when there are indeterminate or weak positive tTG ELISA results
  • In the context of IgA deficiency, testing tTG IgG and/or EMA IgG is recommended
• Deaminated gliadin peptide (DGP) antibodies IgA by ELISA
  • Higher sensitivity/specificity than conventional antigliadin antibody (AGA) 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, presence of tTG IgG and DGP (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; more severe form of disease expected
  • Should be ordered only in patients with confirmed celiac disease by biopsy
• HLA typing
  • 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 celiac disease
      • Found in 40% of general population
      • Absence virtually excludes celiac disease
    • Not necessary for routine laboratory evaluation of celiac disease because of its low positive predictive value
      • Does not improve diagnostic performance of serological testing alone
    • 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
  • 4-5 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

• General population screening is not recommended

• Monitoring adherence to gluten-free diet (GFD) or disease activity
  • tTG and/or DGP IgA and IgG assays
    • Either tTG or /DGP assays can be used depending on previous results in monitoring adherence to a gluten-free diet (GFD)
    • 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

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
• 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

• Aberg AK, Olcen P. Serologic screening for celiac disease in children: a comparison between established assays and tests with deamidated gliadin-derived peptides plus conjugates for both IgA and IgG antibodies. APMIS. 2009; 117 (11) :808-813.PubMed
• Alaedini A, Green PH. Autoantibodies in celiac disease. Autoimmunity. 2008; 41 (1) :19-26.PubMed
• Craig D, Robins G, Howdle PD. Advances in celiac disease. Curr Opin Gastroenterol. 2007; 23 (2) :142-148.PubMed
• Ensari A. Gluten-sensitive enteropathy (celiac disease): controversies in diagnosis and classification. Arch Pathol Lab Med. 2010; 134 (6) :826-836.PubMed
• Ford AC, Chey WD, Talley NJ, Malhotra A, Spiegel BM, Moayyedi P. Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis. Arch Intern Med. 2009; 169 (7) :651-658.PubMed
• Gasbarrini G, Malandrino N, Giorgio V, Fundaro C, Cammarota G, Merra G, Roccarina D, Gasbarrini A, Capristo E. Celiac disease: what's new about it?. Dig Dis. 2008; 26 (2) :121-127.PubMed
• Green PH, Cellier C. Celiac disease. N Engl J Med. 2007; 357 (17) :1731-1743.PubMed
• Harrison MS, Wehbi M, Obideen K. Celiac disease: more common than you think. Cleve Clin J Med. 2007; 74 (3) :209-215.PubMed
• Hopper AD, Hadjivassiliou M, Butt S, Sanders DS. Adult coeliac disease. BMJ. 2007; 335 (7619) :558-562.PubMed
• Losowsky MS. A history of coeliac disease. Dig Dis. 2008; 26 (2) :112-120.PubMed
• McGowan KE, Lyon ME, Butzner JD. Celiac disease and IgA deficiency: complications of serological testing approaches encountered in the clinic. Clin Chem. 2008; 54 (7) :1203-1209.PubMed
• Plebani M, Basso D. Diagnostic testing for celiac disease. JAMA. 2010; 304 (6) :639-640.PubMed
• Prause C, Richter T, Koletzko S, Uhlig HH, Hauer AC, Stern M, Zimmer KP, 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
• Presutti RJ, Cangemi JR, Cassidy HD, Hill DA. Celiac disease. Am Fam Physician. 2007; 76 (12) :1795-1802.PubMed
• Rashtak S, Murray JA. Celiac disease in the elderly. Gastroenterol Clin North Am. 2009; 38 (3) :433-446.PubMed
• Sugai E, Hwang HJ, Vazquez H, Smecuol E, Niveloni S, Mazure R, Maurino 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) :661-665.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) :1738-1746.PubMed
• Vermeersch P, Coenen D, Geboes K, Marien 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) :13-17.PubMed
• Zawahir S, Safta A, Fasano A. Pediatric celiac disease. Curr Opin Pediatr. 2009; 21 (5) :655-660.PubMed

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) :2728-2730.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) :108-111.PubMed

Behçet Syndrome
Dermatitis Herpetiformis
Diarrhea, Bacterial Evaluation
Diarrhea, Parasitic Evaluation
Diarrhea, Viral Evaluation
Food Allergies
Helicobacter pylori
Inflammatory Bowel Disease
Inflammatory Myopathies
Malabsorption
Neuromyelitis Optica
Osteoporosis