New developments in alpha 1-antitrypsin deficiency

Alpha 1-antitrypsin deficiency is an autosomal codominant condition associated with the development of premature emphysema, chronic liver disease, diseases of arterial vascular tissue such as aneurysm formation, and possibly vasculitis. Whereas unchecked proteolytic activity of neutrophil elastase is the likely etiology of premature emphysema and diseases of arterial vascular tissue, chronic liver disease has only recently been proposed to be due to loop-sheet polymerization of the most common deficiency variant of the alpha 1-antitrypsin molecule, the PI*ZZ mutant. Recent evidence suggests that this disorder is underrecognized by health care providers with only 4% of the estimated 60,000 to 100,000 Americans having been identified. Intravenous augmentation therapy with purified pooled plasma derived alpha 1-antitrypsin has been shown to have biochemical efficacy in raising serum and alveolar lining fluid levels to above protective thresholds. Although uncontrolled studies suggest additional clinical efficacy, no randomized clinical trials of intravenous augmentation therapy have been reported to date. The use of gene therapy is currently limited by difficulties in obtaining sustained and therapeutic levels of alpha 1-antitrypsin expression. Alpha 1-antitrypsin deficiency accounts for 11% of all lung transplants performed, with post-transplantation survival rates of 45% at 5 years matching those of lung transplantation for chronic obstructive pulmonary disease in general. These recent advances raise further challenges such as the role of population screening, the prospects of newer therapies such as inhaled augmentation and gene therapy, and the feasibility of randomized placebo-controlled clinical trials.