What causes alpha-1 antitrypsin deficiency?Alpha-1 antitrypsin deficiency results from a genetic defect. The mechanism that causes associated liver disease and emphysema in some people with this deficiency is not known, however some evidence suggests that it may be related to inflammation. Approximately 75% of adults with severe deficiency will develop emphysema, which often begins before 40
years of age. Smoking can increase risk.
Alpha-1 antitrypsin deficiency is caused by a mutation in the proteinase inhibitor (PI) gene on chromosome 14. The normal protein coded for by this gene is involved in tissue repair. Disorder symptoms depend on which type of mutation an individual has in the PI gene. There are more than 70 different alleles of the PI gene. The M allele is the most common non-disease causing (normal) variant. The mutant alleles S and Z are the most common disease-causing variants. Individuals homozygous for the Z allele (PI ZZ) are at high risk for emphysema and liver disease. Individuals homozygous for the S allele (PI SS) do not display symptoms of the disease. However, individuals with one copy of the Z allele and one copy of the S allele (PI SZ) may develop emphysema.
Everyone receives one gene for alpha-1 antitrypsin from each parent. The most common type of alpha-1 antitrypsin gene is the M gene. A person who inherits an M gene from each parent has normal levels of alpha-1 antitrypsin. The Z gene is the most frequent gene that causes the disorder. If a person inherits one M gene and one Z gene, that person is a carrier of the disorder. While such a person may not have normal levels of alpha-1 antitrypsin, there should be enough to protect the lungs. The person who inherits the Z gene from each parent is called "type ZZ." This person has very low alpha-1 antitrypsin levels, allowing elastase to damage the lungs.