pulmonary disorders
Alpha 1 Antitrypsin Deficiency
Pathophysiology of Alpha 1 Antitrypsin Deficiency
Alpha-1 antitrypsin is a neutrophil elastase inhibitor (an antiprotease), the major function of which is to protect the lungs from protease-mediated tissue destruction. Most alpha-1 antitrypsin is synthesized by hepatocytes and monocytes and passively diffuses through the circulation into the lungs; some is secondarily produced by alveolar macrophages and epithelial cells. The protein conformation (and hence functionality) and quantity of circulating alpha-1 antitrypsin are determined by codominant expression of parental alleles;>90 different alleles have been identified and described by protease inhibitor (PI*) phenotype. Inheritance of some variant alleles causes a change in conformation of the alpha-1 antitrypsin molecule, leading to polymerization and retention within hepatocytes. The hepatic accumulation of aberrant alpha-1 antitrypsin molecules causes Neonatal Cholestasis in 10 to 20% of patients; the remaining patients are probably able to degrade the abnormal protein, although the exact protective mechanism is unclear. About 20% of cases of neonatal hepatic involvement result in development of cirrhosis in childhood. About 10% of patients without childhood liver disease develop In the lungs, alpha-1 antitrypsin deficiency increases neutrophil elastase activity, which facilitates tissue destruction leading to emphysema (especially in smokers, because cigarette smoke also increases protease activity). Alpha-1 antitrypsin deficiency accounts for 1 to 2% of all cases of Chronic Obstructive Pulmonary Disease (COPD) (COPD). Alpha-1 antitrypsin deficiency most commonly causes early emphysema; symptoms and signs of lung involvement occur earlier in smokers than in nonsmokers but in both cases are rare before age 25. Some patients with Other disorders possibly associated with alpha-1 antitrypsin allele variants include Panniculitis (an inflammatory disorder of the subcutaneous tissue), life-threatening hemorrhage (through a mutation that converts alpha-1 antitrypsin from a neutrophil elastase to a coagulation factor inhibitor), aneurysms, 