Alpha-1-Antitrypsin Deficiency: A Hereditary Enigma

Alpha- 1-antitrypsin (A-l-AT) is a glycoprotein enzyme inhibitor found in the serum alpha-1-globulins. Production of this compound by the liver is governed by a pair of completely penetrant codominant autosomal alleles. Nine of these variant alleles have been identified and 17 phenotypes, to date, have been discovered. The deficiency state of A-l-AT is not always associated with a disease. In fact, where such data are available, only the Piz allele has been definitely incriminated as being of etiologic significance in the conditions cited below. From surveys of hospital populations in the United States and general populations in Norway it is estimated that the proportions of individuals with the PiZZ genotype (homozygously deficient) range from 0.07 to 0.2%. The two major diseases that have been associated with A-l-AT deficiency are pulmonary emphysema of early onset and juvenile hepatic cirrhosis. In either of these conditions the hepatic cells may contain characteristic deposits of A-l-AT in the form of PAS-positive intracytoplasmic globules: perhaps due to a defect in the carbohydrate moiety, the molecule of A-l-AT does not cross the cell membrane and accumulates in the site of origin. Very recently, A-l-AT has been demonstrated in the alveolar hyaline membranes of neonates who had respiratory distress syndrome. It seems likely that in the future other clinical conditions may be found to be caused by, or associated with, deficiency of this enzyme inhibitor.