Heterozygosity of α₁-Antitrypsin: A Health Risk?

Abstract

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.

Increased risk of chronic liver failure in adults with heterozygous ?-antitrypsin deficiency

“…Forty-one carriers of the heterozygous PI MS variant were observed in our OLT study cohort (6.8%), which is what would be expected by population estimates of prevalence (6%) ( Table 1). 13 The distribution of this phenotype among various disease subcategories revealed no significant statistical differences (data not shown).…”

“…The resultant prevalence of this phenotype was 8.2% (95% CI: 6.1%-10.7%) in our liver transplantation population, which was significantly higher than expected based on prevalence figures (Ϸ3%) estimated by population studies (P Ͻ .0001) ( Table 1). 13,[40][41][42][43][44][45][46][47] Only 2 additional patients were PI*Z heterozygotes (type PI SZ), 1 with alcoholic liver disease, and the other with cryptogenic cirrhosis, but they were not included in this analysis because of the small number.…”

“…Therefore, it is estimated that about 1 in 3,000 white Americans are PI ZZ and 2% to 4% are PI MZ. 1,[11][12][13] Mechanisms of injury in patients with ␣ 1 ATD are now believed to be very different depending on the organ involved. The pathogenesis of lung injury clearly results from a deficiency of antiprotease activity and uninhibited proteolytic attack on lung elastin in the lower respiratory tract.…”

Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed.

“…Recent review articles (Feld 1989;Gourley et al 1989) and research articles (Sandford et al 1999;Sigsgaard et al 2000) provide documentation that both carriers (PiMS and PiMZ) and deficiency allele combinations (PiSS, PiSZ, and PiZZ) are at risk for various adverse health effects. The adverse health effects associated with being a carrier of the PiS defective allele were reviewed in 1989 (Gourley et al 1989), and they included cirrhosis (Lieberman et al 1975), multiple sclerosis (Lolin and Ward 1995), chronic "cryptogenic" liver disease (Carlson and Eriksson 1985), and malignant hepatoma (Carlson and Eriksson 1985).…”

“…In addition, carriers for both defective alleles have been found to be at risk for the development of asthma (Colp et al 1993) and of alcoholic toxic cirrhosis (Spitsyn et al 2001).The fact that carriers for various metabolic diseases such as early vascular disease in homocystinuria, hyperammonemic episodes in ornithine transcarbamylase deficiency, presenile cataracts in galactosemia, and so forth (Endres 1997), as well as for AAT deficiency (Feld 1989;Gourley et al 1989), are at risk for adverse health effects has been well documented. Additional evidence for the risk of developing adverse health effects for carriers of AAT deficiency can also be found in more recent reviews (Gourley et al 1989;Stoller et al 2003).…”