α1-Antitrypsin deficiency and susceptibility to lung disease

Abstract

α1-Antitrypsin (AAT), the major component of α1-globulin, is capable of inhibiting proteolytic enzymes in polymorphonuclear leukocytes (PMN) and pulmonary alveolar macrophages (PAM). AAT is ubiquitously distributed in body fluids and tissues. It is a glycoprotein synthesized in the liver with a molecular weight of 50,000 daltons, a half-life of 3-6 days, and a sedimentation constant of 3.3 S. Enzymes inhibited include elastase, collagenase, thrombin, kallikrein, and chymotrypsin. Serum AAT concentration is determined by multiple codominant alleles. The normal phenotype is M, the most severe deficiency state, Z; intermediate levels are associated with the MZ phenotype. Ethnicity is a major factor in determining phenotypic prevalence. The homozygous Z state occurs in 1/4000-1/8000 Caucasians. Numerous disease processes, mainly involving lungs and liver, have been associated with AAT deficiency. Establishing an uneqivocal etiologic relationship, however, between AAT deficiency and lung disease has been difficult. Studies in this area have varied widely in the number of indivduals included, whether phenotypic analysis, or only quantative determinations, were carried out, in the range of clinical and pulmonary function studies performed and whether the population was community or hospital based. Other confounding variables include the degree of industrial exposure, cigarette smoking, a history of childhood lung disease and levels of proteolytic enzymes in PAMs and PMNs. It has been estimated that about 80% of those with homozygous Z phenotype will develop obstructive pulmonary disease. The prevalence of lung disease in other non-M phenotypes, especially among heterozygotes is uncertain. Those investigations which support, and others which refute, an association will be reviewed. Further investigations, especially those emphasizing levels of proteolytic enzymes, are needed to clarify the interrelationship of these variant phenotypes, environmental risks and the predisposition to chronic obstructive lung disease.