Clinical settings in which human leukocyte antigen typing is still useful in the diagnosis of celiac disease

Celiac disease (CD) is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals. It is characterized by intestinal histological damage and the production of specific autoantibodies. The latest European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2020 guidelines have excluded human leukocyte antigen (HLA) genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value, limited availability, and high cost in some countries. However, HLA genetic testing remains valuable in certain clinical contexts. This study provided practical indications for when to request and how to interpret HLA genotyping, emphasizing its continued relevance for CD diagnosis in specific cases. We also proposed a strategy for monitoring the risk of developing type 1 diabetes (T1D) in patients with CD, based on the risk stratification carried by different HLA genotypes. A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in 2012, when HLA genotyping became mandatory for the diagnosis of CD. We identified key clinical scenarios where HLA testing remains useful. Several high risk HLA-DQ genotypes strongly associated with CD were highlighted, including HLADQ2.5/HLA-DQ2.2 and HLA-DQ2.5/HLA-DQ2.5. Notably, while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD, it appears to confer protection against T1D. To support clinical practice, we presented a table clarifying commonly used HLA terminology, and another summarized the main clinical situations in which HLA genotyping should still be considered. These findings underscore the dual role of HLA testing: Not only can it help rule out CD in selected cases, but it also identifies patients with CD at risk for T1D, guiding personalized monitoring strategies.