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Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency

James K Stoller, MD, MS
Section Editor
Peter J Barnes, DM, DSc, FRCP, FRS
Deputy Editor
Helen Hollingsworth, MD


Alpha-1 antitrypsin (AAT) deficiency is a clinically under-recognized inherited disorder affecting the lungs, liver, and rarely, skin. In the lungs, AAT deficiency causes chronic obstructive pulmonary disease (ie, emphysema and bronchiectasis).

The pulmonary manifestations, diagnosis, and natural history of this disorder will be reviewed here [1-4]. Extrapulmonary disease and therapy are discussed separately. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency" and "Treatment of alpha-1 antitrypsin deficiency".)


AAT is a protease inhibitor (Pi) of the proteolytic enzyme elastase and also of the proteases trypsin, chymotrypsin, and thrombin [5]. It is part of a larger family of structurally unique serine protease inhibitors, referred to as serpins, which have also been implicated in the pathogenesis of neurodegenerative diseases, angioedema, and coagulation abnormalities, collectively called “serpinopathies” [4,6].

Emphysema in AAT deficiency is thought to result from an imbalance between neutrophil elastase in the lung, which destroys elastin, and the elastase inhibitor AAT, which protects against proteolytic degradation of elastin. This mechanism is called a “toxic loss of function.” Specifically, cigarette smoking and infection increase elastase production in the lung, thus increasing lung degradation [4]. In addition, the polymers of “Z” antitrypsin are chemotactic for neutrophils, which may contribute to local inflammation and tissue destruction in the lung [7].

The pathogenesis of the liver disease is quite different and is called a “toxic gain of function.” The liver disease results from the accumulation within the hepatocyte of unsecreted variant AAT protein. Only those genotypes associated with pathologic polymerization of AAT within the endoplasmic reticulum of hepatocytes produce disease [8-10]. Most patients are homozygous for the Z allele (ie, PI*ZZ); liver disease does not occur in null homozygotes who have severe AAT deficiency but no intra-hepatocytic accumulation. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)


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Literature review current through: Sep 2016. | This topic last updated: Mar 17, 2016.
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