Priorities for the alpha-1 community: The physicians perspective

Abstract

Alpha-1 antitrypsin (AAT) deficiency is a clinically under-recognized hereditary disorder with multi-system manifestations, most prominently in the lungs and liver. A rare skin manifestation is also described. The AAT protein is synthesized in the liver and to a lesser extent in macrophages and neutrophils. AAT is the physiological inhibitor of a variety of proteases most notably neutrophil elastase (NE). Unopposed, NE and other proteases attack the lung matrix causing structural damage and markedly impairing host defence. In the commonest form of AAT deficiency the mutated Z AAT is improperly folded, polymerises and aggregates in the liver. As a result less AAT is secreted into the bloodstream and gets to the lungs. This results in liver disease due to AAT aggregation in the liver and pulmonary damage due to the deficiency in the lung rendering it unable to protect against NE-mediated damage. In this review we will discuss AAT deficiency in detail, outlining the pathogenesis, and the clinical manifestations of the condition.