Chapter 219

## Abstract

Abstract

1. α1-Antitrypsin (α1AT), a glycoprotein of molecular mass 52 kDa, is a major plasma serine protease inhibitor (serpin). The major physiological substrate is elastase, particularly in the lower respiratory tract.

2. The locus (PI locus) for α1AT is on chromosome 14 at 14q32.1, in a cluster of sequence-related genes, which includes those for corticosteroid-binding globulin, α1-antichymotrypsin, protein C inhibitor, and kallistatin. The gene is 12.2 kb long and contains six introns. α1AT produced in hepatocytes has a 1.4-kb mRNA transcript, while macrophages and the cornea have a longer RNA transcript, beginning in exons 5′ to the first exon for hepatocyte α1AT.

3. α1AT shows considerable genetic variability, having more than 70 genetic variants (PI types), many of which have been sequenced. The majority of variants are associated with quantitatively and qualitatively normal α1AT. Further variation can be revealed at the DNA level, where a number of restriction enzymes reveal polymorphisms.

4. The PI*Z allele is the most common deficiency variant. PI ZZ homozygotes have 15 to 20 percent of the normal plasma concentration of α1AT, with a corresponding reduced concentration in bronchoalveolar lavage fluid. The deficiency is due to lack of secretion of Z α1AT from the hepatocyte, where inclusions are formed in the rough endoplasmic reticulum. There are several rare deficiency types, including those that show lack of secretion, and those that have no product (null or Q0).

5. Liver inclusions are formed because of a tendency for Z α1AT to self-aggregate. This occurs because the mobile reactive center loop of one protein molecule inserts into that of another molecule, instead of its own, especially at body temperature.

6. A deficiency of α1AT results in a protease/protease inhibitor imbalance in the lung, allowing destruction of the alveolar wall. The resultant obstructive lung disease is the most prevalent clinical manifestation of α1AT deficiency. Basal lung regions are most severely affected. In nonsmokers, onset of dyspnea occurs at a mean age of 45 to 50 years, and in smokers at about 35 years of age. Smokers show a considerably increased rate of lung destruction and have a poorer survival rate than nonsmokers with the deficiency. Smoking enhances oxidation and inactivation of α1AT in the lung.

7. Symptoms of liver abnormalities in infancy are expressed in about 17 percent of all individuals with α1AT deficiency. Only a few percent of all patients with the deficiency have a poor prognosis following early liver symptoms. Other genetic and environmental factors may influence the prognosis.

8. α1AT appears to be involved in regulation of the immune system, perhaps through the production of proteases by T cells. The deficiency state may contribute to diseases with an immune component. Response to inflammation is also impaired.

9. Prenatal diagnosis can be carried out using the polymerase chain reaction, followed by using synthetic oligonucleotide probes, digests with restriction enzymes, or sequencing.

10. Avoidance of smoking is important preventative therapy. Replacement therapy with α1AT, by infusion or aerosol, is effective at increasing protease inhibition in the pulmonary alveoli. Antioxidants could potentially delay lung and liver destruction. Lung and liver transplants offer potential therapy for end-stage destruction of these organs.

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