The Spectrum of Celiac Disease: Epidemiology, Clinical Aspects and Treatment

Greetje J. Tack; Wieke H. M. Verbeek; Marco W. J. Schreurs; Chris J. J. Mulder

Disclosures
In This Article

Diagnosis

Given the broad clinical spectrum of celiac disease, accurate histological and serological testing is essential for correct diagnosis. The diagnosis algorithm of celiac disease currently follows the revised ESPGHAN criteria, published in 1990.[49] Briefly, a positive diagnosis is made when the following features are both present: typical small-intestinal histopathological abnormalities defined as hyperplastic villous atrophy, and clinical remission on a strict gluten-free diet with relief of symptoms within weeks. In asymptomatic individuals a second biopsy is required to verify mucosal recovery after withdrawal of dietary gluten. The presence of circulating celiac-disease-associated antibodies at time of diagnosis and their normalization after a gluten-free diet support a diagnosis of celiac disease. As a consequence of the increased appreciation of the variable clinical and histological manifestations of the disease and improvement of serological and genetic tests, further revision of the ESPGHAN criteria that takes into account the results of multicenter studies has been repeatedly advocated.[10,50]

Appropriate diagnosis of celiac disease is extremely important to avoid lifelong unnecessary commitment to a gluten-free diet in patients with other gastrointestinal diseases and to enable rapid treatment of patients with celiac disease, which decreases the risk of complications.

Histopathological Analysis

Histopathological analysis of small intestinal biopsy samples of individuals with celiac disease is characterized by typical architectural abnormalities. These are classified according to the modified Marsh classification:[51] normal mucosa (Marsh 0), intraepithelial lymphocytosis (Marsh I), intraepithelial lymphocytosis and crypthyperplasia (Marsh II), and intraepithelial lymphocytosis, crypthyperplasia and villous atrophy (Marsh III). Mucosal villous atrophy has long been considered the hallmark of celiac disease and remains the gold standard in celiac disease diagnosis. False-positive and false-negative diagnosis, however, may occur as a consequence of interobserver variability, patchy mucosal damage, low-grade histopathological abnormalities and technical limitations.[52] For example, patients with low-grade histopathological abnormalities (Marsh I or Marsh II) can present with gluten-dependent symptoms or disorders before overt villous atrophy occurs. Furthermore, several patients with isolated intraepithelial lymphocytosis (Marsh I), who are not clinically suspected of having celiac disease, develop celiac disease during follow-up.[50] Although the mucosal changes in celiac disease are thought to develop gradually, whether minor mucosal lesions in asymptomatic patients indicate celiac disease in an early stage is not yet clear.[53] In case of strong clinical suspicion of celiac disease, duodenal biopsy must be performed regardless of serological analysis;[54] in cases of low suspicion of disease or screening, duodenal biopsy only needs to be performed in seropositive patients (Figure 1).

Figure 1.

Algorithm for diagnosis of uncomplicated celiac disease. Abbreviations: EMA, endomysial antibodies; TGA, tissue transglutaminase antibodies.

Serological and Genetic Analyses

At present the most sensitive and specific serological tests for diagnosis of celiac disease are assessments of the presence of IgA autoantibodies against the endomysium of connective tissue (EMA) and against tissue transglutaminase (TGA).[51] Tests for antibodies against deamidated gliadin peptides (which are part of gluten) have also become available and are promising diagnostic tools.[55] At diagnosis stage, at least anti-TGA antibodies should be measured and, if detected, the diagnosis of celiac disease should be preferably verified with assessment of anti-EMA antibodies. Assessment of gliadin antibodies is a less specific and sensitive test than anti-TGA and anti-EMA testing, except in children younger than 2 years of age, in whom measurement of antibodies to gliadin is a more sensitive test.[56] An important pitfall in serological testing for celiac disease is the increased prevalence of IgA deficiency observed in patients with the disease compared with that in healthy individuals.[57] In order to avoid false-negative serological results in cases of IgA deficiency, simultaneous monitoring of serum IgA levels is required. In case of IgA deficiency, screening for IgG antibodies (either to TGA or to EMA) should be performed.[58]

Although HLA-DQ2 and/or HLA-DQ8 positivity is not an absolute requirement for diagnosis, as 40% of the healthy Western population also carry genotypes for these molecules,[8] celiac disease is highly unlikely in case both of them are absent. As a consequence of this high negative predictive value for developing celiac disease, HLA genotyping was proposed as a contributing element to diagnosis, in particular in the absence of villous atrophy.[59] Case-finding of patients with low-grade histopathological features of celiac disease needs to be extended so that clinical studies that investigate the precise role of genotyping as a first-line examination in the diagnostic work-up can be started.

Furthermore, as negative serological testing does not exclude the development of celiac disease later in life, HLA genotyping has also been suggested as a powerful screening tool.[60] Nevertheless, this screening strategy does not seem cost-saving compared with first-line serological screening, although it might prevent unnecessary anti-TGA and anti-EMA diagnostic testing.[61] The Dutch Medical Celiac Disease Society recommends serologic testing in genetically susceptible patients for at least IgA antibodies against TGA every 2 and 5 years in adults and children, respectively.[62]

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