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Extrapulmonary manifestations 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) is a serine protease inhibitor (PI) that is produced in hepatocytes. AAT deficiency is characterized by autosomal co-dominant inheritance of mutations in the alpha-1 antitrypsin gene (MIM 107400) [1]. AAT deficiency is associated with lung, liver, and skin disease.

The extrapulmonary manifestations of AAT deficiency will be reviewed here. The pulmonary manifestations and treatment of AAT deficiency are discussed separately. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Treatment of alpha-1 antitrypsin deficiency".)

The American Thoracic Society (ATS) and European Respiratory Society (ERS) statement on the diagnosis and management of AAT deficiency, as well as other ATS guidelines, can be accessed through the ATS web site at www.thoracic.org/statements.


Liver disorders, such as neonatal hepatitis, cirrhosis both in children and adults, and hepatocellular carcinoma are associated with some alpha-1 antitrypsin (AAT)-deficient genotypes [2-7]. Approximately 10 to 15 percent of newborns are at risk for developing some form of hepatic disease, and approximately 10 to 15 percent of adults develop hepatic disease [8]. Among never smokers, the prevalence of liver disease at death is higher (28 percent) [9].

The two alleles that are best described to confer risk for liver disease, Z and M(malton), are associated with accumulation of AAT protein in the hepatocyte. Other rare alleles, M(duarte), M(nichinan), S, and S(iiyama), are also known to cause intrahepatocytic accumulation [8,10-12]. Liver disease has not yet been described in these latter disorders, but too few individuals have been identified to reach a conclusion [11,13]. The PI Null (Hong Kong) is a variant in which no serum AAT is detected, but truncated protein can be found in the endoplasmic reticulum in the hepatocyte in vitro. Whether clinical liver disease can accompany this variant is unclear based on sparse clinical experience [14].

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Literature review current through: Nov 2017. | This topic last updated: Dec 19, 2016.
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