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Irene Belmonte,1 Alexa Nuñez,1,2 Miriam Barrecheguren,1 Cristina Esquinas,1 Mònica Pons,3 Rosa M López-Martínez,4 Gerard Ruiz,4 Albert Blanco-Grau,4 Roser Ferrer,4 Joan Genescà,3,5 Marc Miravitlles,1,6 Francisco Rodríguez-Frías4 1Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 2Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès). Barcelona, Spain; 3Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron; Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 4Department of Clinical Biochemistry, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain; 6CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, SpainCorrespondence: Marc MiravitllesPneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, P. Vall d’Hebron 119-129, Barcelona 08035, SpainEmail marcm@separ.esBackground: Alpha-1 antitrypsin deficiency (AATD) remains largely underdiagnosed despite recommendations of healthcare institutions and programmes designed to increase awareness. The objective was to analyse the trends in AATD diagnosis during the last 5 years in a Spanish AATD reference laboratory.Methods: This was a retrospective revision of all alpha-1 antitrypsin (AAT) determinations undertaken in our laboratory from 2015 to 2019. We analysed the number of AAT determinations performed and described the characteristics of the individuals tested, as well as the medical specialties and the reasons for requesting AAT determination.Results: A total of 3507 determinations were performed, of which 5.5% corresponded to children. A significant increase in the number of AAT determinations was observed from 349 in 2015 to 872 in 2019. Among the samples, 57.6% carried an intermediate AATD (50– 119 mg/dL) and 2.4% severe deficiency (< 50 mg/dL). The most frequent phenotype in severe AATD individuals was PI*ZZ (78.5%), and aminotransferase levels were above normal in around 43% of children and 30% of adults. Respiratory specialists requested the highest number of AAT determinations (31.5%) followed by digestive diseases and internal medicine (27.5%) and primary care physicians (19.7%). The main reason for AAT determination in severe AATD adults was chronic obstructive pulmonary disease (41.7%), but reasons for requesting AAT determination were not reported in up to 41.7% of adults and 58.3% of children.Conclusion: There is an increase in the frequency of AATD testing despite the rate of AAT determination remaining low. Awareness about AAT is probably increasing, but the reason for testing is not always clear.Keywords: alpha-1 antitrypsin deficiency, diagnosis, screening, lung disease

Irene Belmonte,1,2 Miriam Barrecheguren,3 Rosa M López-Martínez,4 Cristina Esquinas,3 Esther Rodríguez,3,5 Marc Miravitlles,3,5 Francisco Rodríguez-Frías1,6 1Liver Pathology Unit, Department of Biochemistry and Microbiology, Hospital Universitari Vall d´Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 2Vall d´Hebron Institut de Recerca (VHIR), Barcelona, Spain; 3Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 4Biochemistry Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 5CIBER of Respiratory Diseases, Barcelona, Spain; 6CIBER of Liver and Digestive Diseases, Instituto Nacional de Salud Carlos III, Madrid, Spain Background and objectives: Alpha-1-antitrypsin deficiency (AATD) is associated with a high risk for the development of early-onset emphysema and liver disease. A large majority of subjects with severe AATD carry the ZZ genotype, which can be easily detected. Another rare pathologic variant, the Mmalton allele, causes a deficiency similar to that of the Z variant, but it is not easily recognizable and its detection seems to be underestimated. Therefore, we have included a rapid allele-specific genotyping assay for the detection of the Mmalton variant in the diagnostic algorithm of AATD used in our laboratory. The objective of this study was to test the usefulness of this new algorithm for Mmalton detection. Materials and methods: We performed a retrospective revision of all AATD determinations carried out in our laboratory over 2 years using the new diagnostic algorithm. Samples with a phenotype showing one or two M alleles and AAT levels discordant with that phenotype were analyzed using the Mmalton allele-specific genotyping assay. Results: We detected 49 samples with discordant AAT levels; 44 had the MM and five the MS phenotype. In nine of these samples, a single rare Mmalton variant was detected. During the study period, two family screenings were performed and four additional Mmalton variants were identified. Conclusion: The incorporation of the Mmalton allele-specific genotyping assay in the diagnostic algorithm of AATD resulted in a faster and cheaper method to detect this allele and avoided a significant delay in diagnosis when a sequencing assay was required. This methodology can be adapted to other rare variants. Standardized algorithms are required to obtain conclusive data of the real incidence of rare AAT alleles in each region. Keywords: rare variant, emphysema, genotyping, phenotyping, serum levels