What causes alpha 1-antitrypsin deficiency?
Alpha-1 antitrypsin deficiency is an inherited condition caused by a defective gene on chromosome 14. Genes are the sequences of DNA carried in chromosomes in the nucleus of cells. Alpha1 antitrypsin deficiency is hereditary. In order to have the disease, a child must inherit two defective genes, one from each parent.
People who have only one gene for alpha-1-antitrypsin deficiency do not have the disease, but they are "carriers" of the deficiency. Their alpha-1-antitrypsin levels are lower than normal, but this does not cause any obvious health problems. In families where both parents are carriers of the gene for the disease, there is a one in four risk that a child will have alpha-1-antitrypsin deficiency. Over 70 different variants of alpha-1 antitrypsin have been identified. In laboratory tests normal alpha-1 antitrypsin is labelled M.
The major biochemical activity of the AAT molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G), and, therefore, the protein is more accurately termed alpha1 antiprotease. However, most physicians, and virtually all patients, refer to the disease as AAT deficiency. e protein is synthesized predominantly by hepatocytes. After its release from the liver, it circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principle function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particulates in the alveolus. Alpha1 antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction.
In healthy persons, alpha1 antiprotease serves as a protective screen that prevents alveolar wall destruction. Individuals with the AAT genetic defect do not release alpha1 antiprotease from the liver, and the alveoli lack protection. The imbalance of proteases-antiproteases in the alveolus leads to unimpeded neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.
Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years by increasing the number of neutrophils in the alveolus and inactivating the remaining small amounts of antiprotease. he production of alpha1 antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. Nearly 24 variants of the alpha1 antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1 antiprotease (serum levels of 20-53 mmol/L). Deficient levels of alpha1 antiprotease are associated with allele Z (homozygous PiZ, serum level 3.4-7 mmol/L). Serum levels greater than 11 mmol/L appear. |
