Clinical Chemistry 50, No. 12, 2004 2407 lating AAT increases rapidly to concentrations exceeding 2 g/L in response to a wide range of inflammatory conditions, infections, cancer, liver disease, or pregnancy (4–6). When the AAT concentration in plasma decreases to 0.7 g/L, the individual is considered AAT-deficient (7). To date, more than 75 alleles have been identified, of which at least 20 affect either the amount or function of the AAT molecule (8). A protein inhibitor (Pi) system has been developed to describe the various allelic variants; this system is based on the migration of the protein in an electric field (9). The position of the migrated protein is given a letter designation. The most common variant, Pi M (ie, AAT migrates in the middle), is present in 95% of the Caucasian US population and is regarded as the variant associated with normal serum concentrations of functional AAT. The concentration of circulating AAT in the MM phenotype is therefore assigned a relative value of 100%. Heterozygous or homozygous combinations have AAT serum concentrations corresponding to 50%(MZ), 37.5%(SZ), 65%(SS), and 15%(ZZ) of this MM value, respectively (10, 11). More than 90% of clinical cases of severe AAT deficiency are caused by the homozygous Z variant (11, 12). The clinical role of intermediate deficiency (MZ and SZ) of AAT is less clear. A single amino acid substitution in the Z AAT molecule (Glu342Lys) makes it susceptible to spontaneous polymerization. The accumulation of Z AAT polymers within the endoplasmic reticulum of hepatocytes causes protein overload, which may lead to neonatal hepatitis, cirrhosis, and hepatocellular carcinoma (13). Individuals homozygous for the AAT Z allele have a markedly increased risk of developing lung emphysema that is linked to the lack of proteinase inhibitor and uncontrolled proteolysis