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  Disease summary:

  
  
  
  
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    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.

    
    
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    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, M_malton), 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.

    
    
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    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.

    
    
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    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.

  
  
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  Hereditary basis:

  
  
  
  
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    AAT deficiency is inherited as an autosomal codominant condition.

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

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

  
  
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  Differential diagnosis:

  
  
  
  
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    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.

    
    
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    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.

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:

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

  
  
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  Bronchiectasis

  
  
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  Cirrhosis

  
  
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  Chronic hepatitis

  
  
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  Hepatoma

  
  
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  Neonatal jaundice

  
  
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  Panniculitis

  
  
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  C-ANCA-positive vasculitis

Clinical Characteristics

Chronic Obstructive Pulmonary Disease

Guidelines suggest that all patients with chronic obstructive pulmonary disease (COPD) should be tested for AAT deficiency, which accounts for up to 3% of all cases of COPD. Features that should especially prompt suspicion of and testing for AAT deficiency include early-onset emphysema (eg, age <55 years), COPD in the absence of smoking or trivial smoking, radiographic pattern in which the changes of emphysema (eg, hyperlucency, bullous changes) are more prominent at the lung bases than at the apices, and a family history of liver and/or lung disease (even if other risk factors for these conditions [eg, smoking, alcohol use, etc] are present).

COPD may become manifest in AAT-deficient individuals in their mid-40s. Most individuals with severe AAT deficiency will develop COPD and the rate of decline of forced expiratory volume in 1 second (FEV₁) in AAT-deficient individuals is five- to sixfold faster among AAT-deficient active smokers (109 mL/y) and two- to threefold faster than normal (~54-67 mL/y) among AAT-deficient ex- or never-smokers. Studies of the radiographic pattern of emphysema on chest computed tomography (CT) indicate that approximately two-thirds of PI*ZZ individuals have a basilar-predominant pattern of emphysema and that the remainder has a more usual pattern of upper lobe-predominant emphysema.

Liver Disease

Hepatic manifestations of AAT variants that are associated with intrahepatocyte polymerization (eg, Z, M_malton) include neonatal jaundice, neonatal cirrhosis, chronic hepatitis, cryptogenic cirrhosis, and hepatoma. The rare null variants that are characterized by complete absence of AAT synthesis do not cause liver disease.

Panniculitis

Panniculitis is manifested by painful areas of skin induration with breakdown and liquefaction, often in areas of physical trauma (eg, buttocks, arms, legs, extravasation sites after intravenous catheter placement).

C-ANCA-Positive Vasculitis

There is a higher than expected prevalence of abnormal AAT alleles (eg, Z, S) in individuals with C-ANCA vasculitis. It is speculated that this association with C-ANCA-positive vasculitis relates to the fact that proteinase-3, the presumed antigen in Wegener granulomatosis, is a substrate for AAT and that the deficiency of AAT allows the antigenicity of proteinase-3 to increase.

Screening

In patients with COPD, the prevalence of severe deficiency of AAT may be up to 3%. Guidelines from the American Thoracic Society/European Respiratory Society (with endorsements by the American College of Chest Physicians and the American Association for Respiratory Care) recommend testing (with a level A recommendation) the following groups: all symptomatic adults with fixed airflow obstruction on pulmonary function tests (whether characterized clinically as emphysema, chronic bronchitis, or even asthma with incomplete reversal of airflow obstruction on postbronchodilator spirometry testing), individuals with unexplained liver disease (including in neonates, children, and adults); asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (eg, cigarette smoking, occupational exposure); adults with necrotizing panniculitis; and siblings of an individual with AAT deficiency. Population-based screening (eg, of all newborns) has not been recommended currently.

Because the pathogenetic mechanisms of lung disease and liver disease differ (ie, inadequate antiprotease protection against proteolytic burden in the lung versus toxic gain of function due to sequelae of unsecreted AAT polymers in the hepatocyte), individuals may present with lung disease alone, liver disease alone, or both lung and liver disease.

Results of population-based screening studies suggest that AAT-deficient individuals detected at birth have a lower likelihood of starting or continuing to smoke than age and gender-matched AAT-replete peers, emphasizing the importance of counseling against smoking in affected individuals.

Counseling