Alpha-1-antitrypsin deficiency
Updates to Article Attributes
Alpha-1-antitrypsin (AAT) deficiency is a hereditary metabolic disorder. It is the most common genetic cause of emphysema and metabolic liver disease in children and. It results in the unopposed action of neutrophil elastase and subsequent severe basal pan lobular emphysema and respiratory symptoms. Accumulation of altered A1AT in hepatocytes incites inflammatory response and chronic liver disease.
Clinical presentation
The classic presentation of the disease is with dyspnoea in the 4th to 5th decades of life. Two-thirds of individuals show clinical features but most carriers are asymptomatic.
Pathology
AAT is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the AAT protein is produced in hepatocytes by codominant gene expression on chromosome 14. The AAT protein inhibits neutrophil elastase. In patients with severe deficiency, the neutrophil elastase acts unopposed resulting in damage to the lower respiratory tract. This damage is predominantly basal because of the gravitational distribution of pulmonary blood flow.
Associations
- asthma
- pancreatitis
- aneurysms, including intracranial aneurysms 18
Complications
- cirrhosis with increased risk of hepatocellular carcinoma 19
- AAT deficiency carriers are at 70-100% increased risk of lung cancer 20
Radiographic features
Thoracic manifestations
Radiograph and CT
-
- the emphysema pattern was traditionally thought to be pan-lobular although more recent studies have also suggested a variable pattern to the emphysema
- emphysema may develop in 75-85% of cases 12
- bronchiectasis: up to 40% 9
- frank bullae formation: non-specific feature 13
- bronchial wall thickening: non-specific feature 13
- hepatopulmonary syndrome
Nuclear medicine
Reduced perfusion and ventilation in the lower zones on a V/Q study.
Abdominal manifestations
Hepatic manifestations of this disease are those of cirrhosis.
Treatment and prognosis
Emphysema and cirrhosis are usually considered the most common causes of death 8.
Survival is substantially worse in smokers, who have a 20-year decrease in longevity relative to non-smokers. According to one study, the overall median survival time was ~ 55 years 7.
AAT replacement therapy, most often by weekly intravenous infusions of AAT purified from human plasma, has been used in some situations to partially correct the biochemical defect 14-15.
While randomised, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy 14. It's efficacy in reducing mortality, however, is uncertain 16. Other management strategies include avoidance of smoking and other risk factors for cirrhosis.
Differential diagnosis
The differential will depend on the organ involved:
- for thoracic manifestations: see differential for panlobular emphysema
- for hepatic manifestations: see differential for cirrhosis
-<p><strong>Alpha-1-antitrypsin (AAT) deficiency </strong>is a hereditary metabolic disorder. It is the most common metabolic liver disease in children and results in the unopposed action of neutrophil elastase and subsequent severe basal <a href="/articles/pulmonary-emphysema">emphysema</a> and respiratory symptoms.</p><h4>Clinical presentation</h4><p>The classic presentation of the disease is with dyspnoea in the 4<sup>th</sup> to 5<sup>th</sup> decades of life. Two-thirds of individuals show clinical features but most carriers are asymptomatic.</p><h4>Pathology</h4><p>AAT is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the AAT protein is produced in hepatocytes by codominant gene expression on chromosome 14. The AAT protein inhibits neutrophil elastase. In patients with severe deficiency, the neutrophil elastase acts unopposed resulting in damage to the lower respiratory tract. This damage is predominantly basal because of the gravitational distribution of pulmonary blood flow. </p><h5>Associations</h5><ul>- +<p><strong>Alpha-1-antitrypsin (AAT) deficiency </strong>is a hereditary metabolic disorder. It is the most common genetic cause of emphysema and metabolic liver disease in children. It results in unopposed action of neutrophil elastase and subsequent severe basal pan lobular <a href="/articles/pulmonary-emphysema">emphysema</a> and respiratory symptoms. Accumulation of altered A1AT in hepatocytes incites inflammatory response and chronic liver disease. </p><h4>Clinical presentation</h4><p>The classic presentation of the disease is with dyspnoea in the 4<sup>th</sup> to 5<sup>th</sup> decades of life. Two-thirds of individuals show clinical features but most carriers are asymptomatic.</p><h4>Pathology</h4><p>AAT is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the AAT protein is produced in hepatocytes by codominant gene expression on chromosome 14. The AAT protein inhibits neutrophil elastase. In patients with severe deficiency, the neutrophil elastase acts unopposed resulting in damage to the lower respiratory tract. This damage is predominantly basal because of the gravitational distribution of pulmonary blood flow. </p><h5>Associations</h5><ul>