Heterozygosity of alpha 1-antitrypsin: a health risk?

alpha 1-Antitrypsin is a serum glycoprotein synthesized in the liver. It consists of a single polypeptide chain with a molecular weight of about 52,000. The molecule exhibits great genetic diversity with multiple codominant alleles at a single autosomal locus. The majority of the population expresses the M allele. The Z allele, which is the result of a single amino acid substitution, results in levels of alpha 1-antitrypsin that are only 10 to 15% of normal when inherited in the homozygous state. Two main pathological consequences of this state are liver and lung disease. The homozygous S phenotype has also been associated with reduced alpha 1-antitrypsin levels and pathology. The homozygous Z phenotype has an incidence of about 1 in 1700 in certain European populations. People who are heterozygous for the S or Z allele usually have alpha 1-antitrypsin levels which are about 60% of normal. The combined frequency of these alleles in the population may reach 10 to 15%. This review examines the controversy as to whether these individuals are at increased risk for pathology due to their reduced alpha 1-antitrypsin levels.