The diagnosis of celiac disease (CD) is based on three parameters: clinical case identification, serological screening and confirmation test. In agreement with the last European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria, if clinical spectrum and screening tests are suggestive of CD, the evidence of villous atrophy is sufficient to confirm the diagnosis. To complete the diagnostic work-up, a favourable response to the treatment with a gluten-free diet (GFD) is mandatory. However, total villous atrophy is the extreme condition of a modifying spectrum of intestinal damage that can be revealed only in the severe forms of CD. Of consequence, if the histological analysis is the only confirmation test performed, it is possible to highlight false negative results especially in case of patchy atrophy or in absence of intestinal damage, a feature easily found in latent CD. The technical difficulties (sufficient size of the biopsy fragments, correct orientation and cut), the subjective evaluation and the occurrence of villous atrophy in other pathological conditions (e.g., intolerance to proteins other than gluten and tropical sprue) add further limitations to the histology-based diagnosis of CD. In this scenario, HLA-DQ2 and -DQ8 haplotypes have a high negative predictive value and, thus, their absence allows to exclude CD. Instead, the presence of circulating IgA or IgG (respectively, in immunocompetent individuals and in patients with selective IgA deficiency) anti-endomysial (EMA) and/or anti-tissue transglutaminase (anti-tTG) and their disappearance after a GFD, supports the diagnosis. The new developed IgA anti-actin and IgA/IgG anti-deamidated gliadin peptides tests could add further information for the diagnosis and monitoring of CD patients. However, if used alone, the screening tests are insufficient to diagnose CD. On the other hand, it has been demonstrated that EMA and anti-tTG can be detected in culture media of intestinal biopsies from untreated CD patients, as well as in culture media of intestinal biopsies from treated CD patients after in vitro exposure to the specific antigenic stimulus. Since the sensitivity of the organ culture seems to be greater than the histological analysis, this system has been recently proposed as confirmation test in the diagnostic work-up of CD, even if some conflictual opinions have limited its widespread use. In this section, the advances recently achieved to simplify the management and/or improve the performance of both screening and confirmation procedures of CD diagnosis are reported, critically evaluated and compared between them and with each older
