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Key Points

  • Disease summary:

    • Alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant condition characterized by a decrease in the circulating level of AAT, a member of the serine protease inhibitor (serpin) family of proteins. AAT neutralizes several proteolytic enzymes, most notably neutrophil elastase, which can break down matrix proteins of the lung like elastin. Emphysema results from the unopposed proteolytic burden to the lung that is abetted by decreased levels of AAT.

    • The most common severe deficient variant of the AAT allele (ie, the Z allele) is also characterized by intrahepatocyte polymerization and accumulation of the Z-type AAT protein, with resultant cirrhosis and/or hepatoma. In the genetic variants of AAT deficiency that are characterized by intrahepatocyte accumulation of unsecreted AAT (eg, Z, Mmalton), different pathogenetic mechanisms cause the liver versus the lung disease. Liver disease results from a toxic gain of function, which can trigger cirrhosis and/or hepatoma (by incompletely understood mechanisms). Lung disease results from the unopposed proteolytic burden to the lung that exists when levels of AAT are decreased and worsened by increased lung inflammation, as from cigarette smoking.

    • In addition to associations with emphysema and liver disease as clinical manifestations of AAT deficiency, panniculitis and C-ANCA-positive vasculitis have been established to be associated with AAT deficiency.

    • Guidelines recommend testing for AAT deficiency in all symptomatic adults with fixed airflow obstruction on postbronchodilator spirometry, as well as individuals with panniculitis, patients with otherwise unexplained cirrhosis, unexplained bronchiectasis, and siblings of AAT-deficient individuals.

  • Hereditary basis:

    • AAT deficiency is inherited as an autosomal codominant condition.

    • The gene for AAT, SERPINA1, is located on chromosome 14 (14q32.1).

    • Genetic modifiers of pulmonary risk have been proposed and remain the subject of active investigation.

  • Differential diagnosis:

    • AAT deficiency should be considered in the differential diagnosis of various pulmonary, hepatic, and dermatologic conditions, including emphysema, chronic bronchitis, bronchiectasis, or even asthma in which a component of fixed airflow obstruction exists, panniculitis, cirrhosis, chronic hepatitis, hepatoma, and C-ANCA-positive vasculitis.

    • While AAT deficiency should be considered in all symptomatic adults with fixed airflow obstruction, features of emphysema that might further heighten suspicion include basilar-predominant hyperlucency on chest imaging, early-onset emphysema (eg, before age 55), occurrence of emphysema in a non- or trivial-smoker, or a family history of liver or lung disease.

Table 115-1Genetic Differential Diagnosis

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for Alpha-1 Antitrypsin Deficiency

Subjects may be asymptomatic and unaffected. However, affected individuals may have one or more of the following clinical manifestations that have been found to be associated with AAT deficiency:

  • Chronic obstructive pulmonary disease (eg, emphysema, chronic bronchitis)

  • Bronchiectasis

  • Cirrhosis

  • Chronic ...

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