Alpha-1-antitrypsin (A1AT) deficiency is a hereditary metabolic disorder and is the most common genetic cause of emphysema and metabolic liver disease in children. It results in the unopposed action of neutrophil elastase and subsequent severe basal panlobular emphysema and respiratory symptoms. Accumulation of altered alpha-1-antitrypsin in hepatocytes incites an inflammatory response and chronic liver disease.
The classic presentation of the disease is with dyspnea in the 4th to 5th decades of life. Two-thirds of individuals show clinical features but most carriers are asymptomatic.
Alpha-1-antitrypsin (A1AT) is a protein that prevents enzymes such as elastase from degrading normal host tissue. Over 90% of the alpha-1-antitrypsin protein is produced in hepatocytes by codominant gene expression on chromosome 14. The alpha-1-antitrypsin 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.
Plain radiograph and CT
- the emphysema pattern was traditionally thought to be panlobular, although more recent studies have also suggested a variable pattern to the emphysema
- basal predominance, in contradistinction to centrilobular emphysema, which shows apical predominance; the two conditions can coexist in smokers
- 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
Reduced perfusion and ventilation in the lower zones on a ventilation/perfusion (V/Q) study.
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.
Alpha-1-antitrypsin replacement therapy, most often by weekly intravenous infusions of alpha-1-antitrypsin purified from human plasma, has been used in some situations to partially correct the biochemical defect 14,15.
While randomized, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy 14, its efficacy in reducing mortality is uncertain 16. Other management strategies include avoidance of smoking and of other risk factors for cirrhosis.
- cirrhosis with increased risk of hepatocellular carcinoma 19
- A1AT deficiency carriers are at 70-100% increased risk of lung cancer 20
The differential will depend on the organ involved:
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