Transglutaminase and endomysium antibodies in diagnosis of celiac disease

Evidence Summaries for Current Care Guidelines
Jorma Komulainen and Katriina Kukkonen-Harjula

Level of evidence: A

High concentrations of IgA transglutaminase antibodies (TGA) in addition with positivity for IgA endomysial antibodies (EmA) are highly diagnostic for celiac disease.

The aim of the systematic review and meta-analysis was to report about the evidence on comparative accuracy and safety of methods used in current clinical practice to diagnose celiac disease, including serological tests, human leukocyte antigen (HLA) typing, and video capsule endoscopy «Maglione MA, Okunogbe A, Ewing B ym. 2016;: ...»2. Diagnostic tests used singly and in combination in various populations were compared against the reference standard of endoscopic duodenal biopsy. A total of 60 individual studies and 13 systematic reviews were included.

New meta-analyses found high-strength evidence to support excellent accuracy of anti-tissue transglutaminase (tTG) immunoglobulin A (IgA) tests (specificity 97.9%) and excellent specificity of endomysial antibodies (EmA) IgA tests (specificity 99.0%), as reported in previous systematic reviews.

  • Study quality: High
  • Applicability: Good for symptomatic patients.

The ESPGHAN published new guidelines for criteria in diagnosis of celiac disease (CD) in children in 2012 «Husby S, Koletzko S, Korponay-Szabó IR ym. Europea...»5. Guidelines were based on a comprehensive literature review «Giersiepen K, Lelgemann M, Stuhldreher N ym. Accur...»7 and consensus of 17 experts' consensus based on the Delphi process.

In children with symptoms suggestive for CD, the diagnosis is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titres are high (>10 times upper level for normal, ULN), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory testing (positive EmA levels in a consecutive blood sample, consider testing for HLA-DQ2/DQ8).

In children without symptoms suggestive for CD, diagnosis is based on positive serology and histology.

  • Study quality: High
  • Applicability: Good

A Finnish study evaluated the utility of ESPGHAN criteria for the diagnosis of celiac disease in at-risk groups «Kurppa K, Salminiemi J, Ukkola A ym. Utility of th...»3. Serum IgA-class RBC-TG2ab and serum IgA-class endomysium antibodies (EmA) were measured in 3031 family members or other relatives of patients with celiac disease. RBC-TG2ab concentrations were classified as weakly (20-29 U), ly (30-99 U), or strongly (100 U or more) positive. Seropositive subjects were further tested by human recombinant TG2ab (Hr-TG2ab) and for the presence of celiac disease-associated HLA-DQ alleles. Gastroscopy was recommended for all with positive RBC-TGab, EmA, or Hr-TG2ab, or weakly positive RBC-TG2ab and symptoms.

Strongly positive RBC-TG2ab had good correlation with EmA, Hr-TG2ab and positivity of HLA-DQ2/8, and the diagnosis was established in 94% of both children and adults at risk.

  • Study quality: High
  • Applicability: Good for relatives of patients with celiac disease.

A Finnish cohort study investigated the association between serum antibody concentrations and subsequent celiac disease (CD) diagnosis in a series of 405 children and adults «Kurppa K, Räsänen T, Collin P ym. Endomysial antib...»4. EmA positivity was the primary inclusion criterion. Besides subjects with classical gastrointestinal presentation of CD, the study cohort included a substantial number of individuals with extraintestinal symptoms and those found by screening in at-risk groups. The antibody values were graded as low (EmA 1:5-200; TG2ab 5.0-30.0 U/L) and high (EmA 1:≥500; TG2ab ≥ 30 U/L).

TG2-ab were measured in 316 EmA positive subjects and proved positive in 91%. Forty-one% of the participants had high EmA and 54% high TG-2ab at baseline. In total, 79% of subjects with low and 94% of those with high EmA titres showed small-bowel mucosal villous atrophy. Furthermore, 96% of the 47 EmA positive subjects who had normal mucosal villi and remained on follow-up, either subsequently developed mucosal atrophy while on gluten-containing diet or responded positively to a gluten-free diet.

  • Study quality: Moderate
  • Applicability: Good
  • Comment: Since EMA ab-negative subjects were not included in the study, the overall sensitivity of the serological tests could not be obtained. However, the interest in the study was in the specificity of the test.

A large, international prospective study targeted to evaluate the ESPGHAN guidelines for diagnosis of celiac disease «Werkstetter KJ, Korponay-Szabó IR, Popp A ym. Accu...»6. Data were collected from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice.

Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (CI, 98.67-99.96) to 100.00 (CI, 99.23-100.00).

  • Study quality: High
  • Applicability: Good


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