Alpha-1 antitrypsin deficiency: current perspective from genetics to diagnosis and therapeutic approaches

Alpha-1 antitrypsin (A1AT) is a 52-kDa, acute phase glycoprotein encoded by the protease inhibitor (PI) locus, located on the long arm of chromosome 14 (14q31-32.3). Its structure is composed of a total of 7 exons, 4 coding (II, III, IV, and V) and 3 non-coding (IA, IB, and IC). A1AT is produced primarily by hepatocytes and acts as a serine protease inhibitor with antiprotease and immunoregulatory activities. The main target of A1AT is neutrophil elastase (NE), an enzyme released during a neutrophil-mediated inflammatory process. When the enzyme is not adequately balanced by A1AT activity, it can cause tissue injury and destruction. A1AT deficiency (A1ATD) is a genetic autosomal recessive disease, characterized by low serum levels of A1AT. The condition may lead to liver disease, early-onset pulmonary emphysema and, rare multi-organ vasculitis, necrotizing panniculitis and fibromyalgia. At least 100 allelic variants of the polymorphic PI locus have been described with groups including associations with different A1AT plasma levels and functions. Treatments with purified A1AT preparations, obtained through pooled human plasma (augmentation therapy), have been proven to improve survival and disease-related quality of life, as well as, slow down the progression of organ damage. Furthermore, ongoing research is now focusing on the development of specifically targeted, new medications. The aim of this review is to summarize our knowledge of the genetic A1AT variants, focusing on their variable clinical manifestation, report routine and recently updated laboratory diagnostic techniques, and to highlight the relevance of early diagnosis of A1ATD. Moreover, we will review the role of augmentation therapy recommendations and future perspectives focusing on a personalized treatment of A1ATD.