by Dr Jacqueline Gosink
In 2022, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published a position paper on the management and follow-up of children and adolescents with coeliac disease (CD), following publication of new guidelines for the diagnosis of CD in 2020. This article discusses the different markers that can be used for the diagnosis and monitoring of CD as well as the ESPGHAN recommendations.
Coeliac disease (CD) is a common autoimmune disease which requires life-long adherence to a gluten-free diet (GFD). A new position paper published in 2022 by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) provides recommendations for follow-up of children and adolescents diagnosed with CD and supplements the diagnostic guidelines published in 2020. Antibodies of class IgA against tissue transglutaminase (TGA-IgA) are the most important diagnostic marker for CD and in the new paper are recommended as the first-line parameter for monitoring patients. In patients with IgA deficiency, CD-specific antibodies of class IgG serve as an alternative. The recommended time interval for follow-up is 3–6 months after start of a GFD and every 6 months thereafter until the antibody level has normalized. The antibody measurements serve as a proxy for mucosal healing and aid assessment of patient compliance with the prescribed diet.
Coeliac disease (CD)
CD is an immunologically mediated systemic disease with a pronounced genetic disposition. Its prevalence is estimated at 0.5–1%, although a large number of undiagnosed cases due to atypical or mild symptoms is suspected. CD is triggered by consumption of gluten, which accounts for around 90% of the protein content of many grain seeds such as wheat, barley or rye. The classic manifestation of CD is severe inflammation of the small-intestinal mucosa characterized by villous atrophy and cryptic hyperplasia. Due to reduced nutrient absorption, a broad spectrum of clinical gastrointestinal and non-gastrointestinal symptoms can develop, including chronic diarrhoea, vomiting, abdominal pain, growth disorders, weight loss, anemia, delayed puberty and osteoporosis. The chronic skin condition dermatitis herpetiformis (Duhring’s disease) can also occur. Risk groups for CD include, for example, first-degree relatives of CD patients and individuals with certain diseases such as type I diabetes mellitus, Down’s syndrome, or selective IgA deficiency. Potential CD refers to cases with CD autoimmunity but no villous atrophy, which may evolve into classic CD. The only effective treatment for CD is a strict GFD to enable regeneration of the small-intestinal mucosa and regression of symptoms.
Key serological markers
TGA-IgA (antibodies of class IgA against tissue transglutaminase) are the most important serological marker in CD. They occur in CD at a prevalence of 95–100% and are virtually never found in healthy individuals or patients with other intestinal diseases. Endomysial antibodies (EMA) directed against endomysium (a connective tissue layer), represent another well-established marker for CD in the context of the indirect immunofluorescence detection method. The main target antigen of these antibodies is transglutaminase (TG).
Components of gluten, especially gliadin, are the exogenous trigger of the inflammatory reactions in CD. Antibodies against deamidated gliadin peptides (DGP) comprise a further sensitive and specific serological marker for CD. Detection of DGP-IgG antibodies is especially useful in patients with an IgA deficiency.
HLA-DQ2 and -DQ8 are the principal determinants of genetic susceptibility for CD and possess a very high negative predictive value for CD. If HLA-DQ2/DQ8 are negative, CD can be as good as excluded. As these alleles occur in around 30% of the healthy population, their determination is used primarily for exclusion diagnostics.
ESPGHAN diagnostic algorithm
The current diagnostic guidelines from ESPGHAN centre on the determination of CD-specific antibodies and in some situations HLA-DQ2/DQ8 alleles . The diagnostic algorithm is applied in children and adolescents with symptoms suggestive of CD as well as in asymptomatic persons with a high risk of CD. The antibody determination must be performed under a gluten-containing diet, as the antibodies steadily decline with a GFD.
TGA-IgA is the recommended first-line test for CD, due to its accuracy and cost-effectiveness. Total IgA is determined in parallel to exclude an IgA deficiency. If the TGA-IgA titer is more than 10 times the upper limit of normal (≥10× ULN) and this result is reinforced by positive EMA-IgA in a second serum sample, an intestinal biopsy is not required. Biopsy remains necessary in children with a TGA-IgA titer of <10× ULN, in cases of suspected CD but negative serology, and for the diagnosis of CD in adults. If total IgA is low, a test for CD-specific IgG (DGP, TGA or EMA) is undertaken along with a biopsy.
HLA-DQ2/DQ8 determination is not obligatory for CD diagnostics but may be useful in some circumstances, such as in patients without high TGA-IgA or patients from risk groups. Gluten challenge is only performed in exceptional circumstances, for example, in children with suspected CD who started a GFD before the diagnosis. HLA-DQ2/DQ8 typing should be performed beforehand to potentially exclude CD. Gluten challenge should be avoided in children and adolescents during periods of accelerated growth.
ESPGHAN follow-up recommendations
According to the new position paper from ESPGHAN, follow-up of children and adolescents with CD after diagnosis is necessary to assess growth and development, resolution of symptoms, possible complications, as well as compliance with the GFD .
Initial follow-up should take place 3–6 months after diagnosis. TGA-IgA measured by ELISA or other enzyme immunoassays is recommended for monitoring CD patients. The TGA-IgA titer usually falls significantly after 3 months of a strict GFD (Fig. 1) and serves as a surrogate marker for mucosal healing. Further tests should be performed every 6 months until the TGA-IgA value has normalized to less than 1 ULN. After this, the TGA-IgA level should be checked every 12–24 months. If no reduction in the TGA-IgA titer is observed after 6–12 months or if slightly elevated levels persistent over a long time, this usually indicates non-compliance with the GFD. For monitoring IgA-insufficient patients, an IgG test for CD-specific antibodies such as DGP, TGA, or EMA should be performed at the same time intervals.