Diagnosis of alpha-1 antitrypsin deficiency: modalities, indications and diagnosis strategy

Alpha-1 antitrypsin (α1-AT) deficiency is an autosomal recessive genetic disorder, which predisposes affected patients to development of pulmonary emphysema or liver cirrhosis. Despite the guidelines from the American Thoracic Society and the European Respiratory Society about α1-AT deficiency screening, it remains significantly under recognized. So, it seems necessary to propose an efficient and suitable biological approach to improve diagnosis and management of α1-AT deficiency. α1-AT is a 52 kDa glycoprotein predominantly produced in the liver and its physiological serum concentration for adults ranges from 0.9 to 2.0g/L (17-39 μmol/L). It is encoded by the SERPINA1 gene, which is highly pleomorphic, and to date, more than 100 alleles have been identified. α1-AT testing would initially involve quantification of serum α1-AT concentration with possible complementary measurement of the elastase inhibitory capacity of serum. If the serum α1-AT concentration is reduced below the reference value, two strategies for laboratory testing can be used: (i) serum α1-AT phenotyping by isoelectric focusing which allows identification of the most common variant designated as the PI M variant but also of various deficient variants besides the predominant PI S and PI Z ones; (ii) genotyping by allele-specific PCR methods which allows only identification of the deficient PI S and PI Z alleles. Identification of the null alleles or of other rare deficient alleles can be performed by direct sequencing of the whole SERPINA1 gene as a reflex test.