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About alpha1-antitrypsin (AAT) deficiency
AAT deficiency, sometimes known simply as “alpha-1”, is a genetic disease primarily affecting the lungs and liver. It is characterised by a decrease in circulating levels of a protein called alpha1 antitrypsin.1
AAT deficiency is the major known genetic risk factor for chronic obstructive pulmonary disease (COPD), particularly emphysema with basilar predominance.2 COPD is characterised by respiratory symptoms that are persistent with a limitation of airflow due to airway or alveoli dysfunction.3
Respiratory symptoms of AAT deficiency are often indistinguishable from smoking-induced COPD or asthma, chronic bronchitis and emphysema (usually in combination), including:4,5
- Excess sputum production
- Severe dyspnoea on exertion
Risks associated with AAT deficiency:
- Chronic obstructive pulmonary disease (COPD)1,6
- Reduced life expectancy1,6
- Cirrhosis in infants, children and adults with specific genetic variants1,6
- Necrotising panniculitis, a rare skin disease1,6
- Wegener's disease (vasculitis)1,6
There are no clinical characteristics that rule out the diagnosis of AAT deficiency, nor predictive clinical, demographic or age-related characteristics that predict a diagnosis of AAT deficiency.7 Because AAT deficiency cannot be diagnosed on clinical presentation alone, it is underdiagnosed and should be confirmed with laboratory testing.6,8-10
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The longer AAT deficiency remains undiagnosed, the greater the risk of irreparable lung damage10,11
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What is alpha1 antitrypsin (AAT)?
AAT (the protein) is a protease inhibitor (Pi), an enzyme, that is produced mainly in the liver. AAT is continuously produced and transported in the bloodstream and can be found at high concentration in the lungs (Figure 1).12 During episodes of inflammation, infection, cancer or during pregnancy, AAT production is increased, so it is known as an acute phase protein.13
Why is AAT critical to protect the lungs?
The most important function of alpha1 antitrypsin is the inactivation of proteolytic enzymes in the lungs (Figure 2). Such enzymes are released during an immune response, which is frequent since the lungs are continuously exposed to airborne pathogens. While these proteolytic enzymes are key for destroying pathogens, if uncontrolled, they have the potential to destroy lung tissue.12
When there is a deficiency of AAT (Figure 3) the excess of these proteolytic enzymes, particularly neutrophil elastase, the lung matrix components, alveolar structures and blood vessels are gradually destroyed. This manifests as chronic obstructive bronchitis or emphysema.12
AAT is critical to protect the lungs12
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What causes liver disease in AAT deficiency?
Certain genetic variants are also associated with liver disease. For example, the PiZ variant is thought to cause the AAT protein to form large polymers that accumulate in the liver cells, causing cellular injury and cell death.12
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AAT: alpha1 antitrypsin; COPD: chronic obstructive pulmonary disease.